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Pharmaceutics, Volume 11, Issue 9 (September 2019)

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Cover Story (view full-size image) The rapid increase of antimicrobial resistance has made it imperative to develop alternative [...] Read more.
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Open AccessArticle
Monitoring of Antimicrobial Drug Chloramphenicol Release from Electrospun Nano- and Microfiber Mats Using UV Imaging and Bacterial Bioreporters
Pharmaceutics 2019, 11(9), 487; https://doi.org/10.3390/pharmaceutics11090487 - 19 Sep 2019
Viewed by 426
Abstract
New strategies are continuously sought for the treatment of skin and wound infections due to increased problems with non-healing wounds. Electrospun nanofiber mats with antibacterial agents as drug delivery systems provide opportunities for the eradication of bacterial infections as well as wound healing. [...] Read more.
New strategies are continuously sought for the treatment of skin and wound infections due to increased problems with non-healing wounds. Electrospun nanofiber mats with antibacterial agents as drug delivery systems provide opportunities for the eradication of bacterial infections as well as wound healing. Antibacterial activities of such mats are directly linked with their drug release behavior. Traditional pharmacopoeial drug release testing settings are not always suitable for analyzing the release behavior of fiber mats intended for the local drug delivery. We tested and compared different drug release model systems for the previously characterized electrospun chloramphenicol (CAM)-loaded nanofiber (polycaprolactone (PCL)) and microfiber (PCL in combination with polyethylene oxide) mats with different drug release profiles. Drug release into buffer solution and hydrogel was investigated and drug concentration was determined using either high-performance liquid chromatography, ultraviolet-visible spectrophotometry, or ultraviolet (UV) imaging. The CAM release and its antibacterial effects in disc diffusion assay were assessed by bacterial bioreporters. All tested model systems enabled to study the drug release from electrospun mats. It was found that the release into buffer solution showed larger differences in the drug release rate between differently designed mats compared to the hydrogel release tests. The UV imaging method provided an insight into the interactions with an agarose hydrogel mimicking wound tissue, thus giving us information about early drug release from the mat. Bacterial bioreporters showed clear correlations between the drug release into gel and antibacterial activity of the electrospun CAM-loaded mats. Full article
(This article belongs to the Special Issue Recent Development of Electrospinning for Drug Delivery)
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Open AccessReview
Injectable Hydrogels for Cancer Therapy over the Last Decade
Pharmaceutics 2019, 11(9), 486; https://doi.org/10.3390/pharmaceutics11090486 - 19 Sep 2019
Viewed by 366
Abstract
The interest in injectable hydrogels for cancer treatment has been significantly growing over the last decade, due to the availability of a wide range of starting polymer structures with tailored features and high chemical versatility. Many research groups are working on the development [...] Read more.
The interest in injectable hydrogels for cancer treatment has been significantly growing over the last decade, due to the availability of a wide range of starting polymer structures with tailored features and high chemical versatility. Many research groups are working on the development of highly engineered injectable delivery vehicle systems suitable for combined chemo-and radio-therapy, as well as thermal and photo-thermal ablation, with the aim of finding out effective solutions to overcome the current obstacles of conventional therapeutic protocols. Within this work, we have reviewed and discussed the most recent injectable hydrogel systems, focusing on the structure and properties of the starting polymers, which are mainly classified into natural or synthetic sources. Moreover, mapping the research landscape of the fabrication strategies, the main outcome of each system is discussed in light of possible clinical applications. Full article
(This article belongs to the Special Issue Functional Polymers for Controlled Drug Release)
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Open AccessArticle
Rational Development of Liposomal Hydrogels: A Strategy for Topical Vaginal Antiretroviral Drug Delivery in the Context of HIV Prevention
Pharmaceutics 2019, 11(9), 485; https://doi.org/10.3390/pharmaceutics11090485 - 18 Sep 2019
Viewed by 737
Abstract
HIV/AIDS stands as a global burden, and vaginal microbicides constitute a promising strategy for topical pre-exposure prophylaxis. Preceding the development of a microbicide containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), in silico and in vitro studies were performed to evaluate the physicochemical [...] Read more.
HIV/AIDS stands as a global burden, and vaginal microbicides constitute a promising strategy for topical pre-exposure prophylaxis. Preceding the development of a microbicide containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), in silico and in vitro studies were performed to evaluate the physicochemical characteristics of both drugs, and to study their biophysical impact in lipid model systems. Results from these pre-formulation studies defined hydrogels as adequate vehicles to incorporate TDF-loaded liposomes and FTC. After studying interactions with mucin, zwitterionic liposomes with a mean diameter of 134 ± 13 nm, an encapsulation TDF efficiency of approximately 84%, and a transition temperature of 41 °C were selected. The chosen liposomal formulation was non-cytotoxic to HEC-1-A and CaSki cells, and was able to favor TDF permeation across polysulfone membranes (Jss = 9.9 μg·cm−2·h−1). After the incorporation of TDF-loaded liposomes and FTC in carbomer hydrogels, the drug release profile was sustained over time, reaching around 60% for both drugs within 3–6 h, and best fitting the Weibull model. Moreover, liposomal hydrogels featured pseudoplastic profiles that were deemed suitable for topical application. Overall, the proposed liposomal hydrogels may constitute a promising formulation for the vaginal co-delivery of TDF/FTC. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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Open AccessArticle
Cutaneous Biodistribution: A High-Resolution Methodology to Assess Bioequivalence in Topical Skin Delivery
Pharmaceutics 2019, 11(9), 484; https://doi.org/10.3390/pharmaceutics11090484 - 18 Sep 2019
Viewed by 390
Abstract
A draft guideline from the European Medicines Agency (EMA) highlights the need for methods to assess the quality/equivalence of topical drug formulations. The “cutaneous biodistribution method”, which provides insight into a drug’s spatial distribution in the epidermis/dermis, was used to compare cutaneous bioavailability [...] Read more.
A draft guideline from the European Medicines Agency (EMA) highlights the need for methods to assess the quality/equivalence of topical drug formulations. The “cutaneous biodistribution method”, which provides insight into a drug’s spatial distribution in the epidermis/dermis, was used to compare cutaneous bioavailability of econazole nitrate (ECZ) from a reference medicinal product (RMP) and two approved bioequivalent generic creams under finite dose conditions. Statistically significant differences between the ECZ biodistributions from the RMP/Generics were determined and used with acceptance criteria based on those from the EMA to evaluate bioequivalence. In porcine skin, ECZ deposition in total skin, epidermis, upper and lower dermis from Generic 1 was within the acceptance interval, contrary to Generic 2, which was marginally below it. For human skin, Generic 1 deposition was marginally above the acceptance interval and not bioequivalent. The results were consistent with those using the EMA’s acceptance intervals using the ratio of the mean ECZ depositions of Generic 1 and the RMP. Differences identified using this data-rich technique may not translate to observable differences in clinical efficacy; however, generics with non-statistically different biodistributions to the RMP should have a comparable clinical effect. The cutaneous biodistribution method could benchmark the development of topical generic products. Full article
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Open AccessArticle
Effects of Electrospinning on the Viability of Ten Species of Lactic Acid Bacteria in Poly(Ethylene Oxide) Nanofibers
Pharmaceutics 2019, 11(9), 483; https://doi.org/10.3390/pharmaceutics11090483 - 18 Sep 2019
Viewed by 393
Abstract
Lactic acid bacteria can have beneficial health effects and be used for the treatment of various diseases. However, there remains the challenge of encapsulating probiotics into delivery systems with a high viability and encapsulation efficacy. The electrospinning of bacteria is a novel and [...] Read more.
Lactic acid bacteria can have beneficial health effects and be used for the treatment of various diseases. However, there remains the challenge of encapsulating probiotics into delivery systems with a high viability and encapsulation efficacy. The electrospinning of bacteria is a novel and little-studied method, and further investigation of its promising potential is needed. Here, the morphology, zeta potential, hydrophobicity, average cell mass, and growth characteristics of nine different species of Lactobacillus and one of Lactococcus are characterized. The electrospinning of polymer solutions containing ~10 log colony forming units (CFU)/mL lactic acid bacteria enabled the successful incorporation of all bacterial species tested, from the smallest (0.74 µm; Lactococcus lactis) to the largest (10.82 µm; Lactobacillus delbrueckii ssp. bulgaricus), into poly(ethylene oxide) nanofibers with an average diameter of ~100 nm. All of these lactobacilli were viable after incorporation into nanofibers, with 0 to 3 log CFU/mg loss in viability, depending on the species. Viability correlated with the hydrophobicity and extreme length of lactic acid bacteria, whereas a horizonal or vertical electrospinning set-up did not have any role. Therefore, electrospinning represents a promising method for the incorporation of lactic acid bacteria into solid delivery systems, while drying the bacterial dispersion at the same time. Full article
(This article belongs to the Special Issue Recent Development of Electrospinning for Drug Delivery)
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Open AccessArticle
Pharmacokinetic Study of NADPH Oxidase Inhibitor Ewha-18278, a Pyrazole Derivative
Pharmaceutics 2019, 11(9), 482; https://doi.org/10.3390/pharmaceutics11090482 - 17 Sep 2019
Viewed by 384
Abstract
In a previous study, the specific NOX1/2/4 inhibitor Ewha-18278 was confirmed as a possible treatment for osteoporosis both in vitro and in vivo. Here, we investigated the pharmacokinetics (PK) of the compound by intravenous (IV) and oral administrations to rats. Dimethyl sulfoxide (DMSO)-based [...] Read more.
In a previous study, the specific NOX1/2/4 inhibitor Ewha-18278 was confirmed as a possible treatment for osteoporosis both in vitro and in vivo. Here, we investigated the pharmacokinetics (PK) of the compound by intravenous (IV) and oral administrations to rats. Dimethyl sulfoxide (DMSO)-based and diazepam injection-based formulations were used to dissolve the compound. In the latter formulation applicable to humans, the changes in PK parameters were monitored at two different concentrations (1 mg/mL and 2 mg/mL). The area under the plasma concentration-time curve from zero time to infinity (AUCinf) of Ewha-18278 was highest in the DMSO-based formulation (2 mg/mL). Also, the concentration was increased 1.6-fold at the low concentration of the diazepam injection-based formulation compared to the high concentration. There was no statistical significance in the AUCinf of the compound between DMSO-based formulation (2 mg/mL) and diazepam injection-based formulation (1 mg/mL). These results suggest that Ewha-18278 can be delivered to humans by both IV and oral routes. In addition, the diazepam injection-based formulation of Ewha-18278 appears to be a suitable candidate for dosage development for future toxicity test and clinical trial. Full article
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Open AccessArticle
Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors
Pharmaceutics 2019, 11(9), 481; https://doi.org/10.3390/pharmaceutics11090481 - 17 Sep 2019
Viewed by 557
Abstract
The blood-brain barrier (BBB) poses a major obstacle by preventing potential therapeutic agents from reaching their intended brain targets at sufficient concentrations. While transient disruption of the BBB has been used to enhance chemotherapeutic efficacy in treating brain tumors, limitations in terms of [...] Read more.
The blood-brain barrier (BBB) poses a major obstacle by preventing potential therapeutic agents from reaching their intended brain targets at sufficient concentrations. While transient disruption of the BBB has been used to enhance chemotherapeutic efficacy in treating brain tumors, limitations in terms of magnitude and duration of BBB disruption exist. In the present study, the preliminary safety and efficacy profile of HAV6, a peptide that binds to the external domains of cadherin, to transiently open the BBB and improve the delivery of a therapeutic agent, was evaluated in a murine brain tumor model. Transient opening of the BBB in response to HAV6 peptide administration was quantitatively characterized using both a gadolinium magnetic resonance imaging (MRI) contrast agent and adenanthin (Ade), the intended therapeutic agent. The effects of HAV6 peptide on BBB integrity and the efficacy of concurrent administration of HAV6 peptide and the small molecule inhibitor, Ade, in the growth and progression of an orthotopic medulloblastoma mouse model using human D425 tumor cells was examined. Systemic administration of HAV6 peptide caused transient, reversible disruption of BBB in mice. Increases in BBB permeability produced by HAV6 were rapid in onset and observed in all regions of the brain examined. Concurrent administration of HAV6 peptide with Ade, a BBB impermeable inhibitor of Peroxiredoxin-1, caused reduced tumor growth and increased survival in mice bearing medulloblastoma. The rapid onset and transient nature of the BBB modulation produced with the HAV6 peptide along with its uniform disruption and biocompatibility is well-suited for CNS drug delivery applications, especially in the treatment of brain tumors. Full article
(This article belongs to the Special Issue Drug Delivery Technology Development in Canada)
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Open AccessArticle
Development and Characterization of Eudragit®-Based Electrospun Nanofibrous Mats and Their Formulation into Nanofiber Tablets for the Modified Release of Furosemide
Pharmaceutics 2019, 11(9), 480; https://doi.org/10.3390/pharmaceutics11090480 - 17 Sep 2019
Viewed by 398
Abstract
Furosemide, a chloride channel blocker ordinarily used as a high-ceiling or loop diuretic, is practically insoluble in water and dilute acids. Due to its acidic nature, furosemide is mostly absorbed in the stomach and in the upper small intestine. Efforts have focused on [...] Read more.
Furosemide, a chloride channel blocker ordinarily used as a high-ceiling or loop diuretic, is practically insoluble in water and dilute acids. Due to its acidic nature, furosemide is mostly absorbed in the stomach and in the upper small intestine. Efforts have focused on the development of sustained release systems of furosemide in order to improve the effectiveness of the drug, which exhibits poor aqueous solubility and poor permeability. Recently, electrospun nanofibrous drug delivery systems have emerged as promising alternative solid-dosage forms due to their advantages of high porosity, high surface to volume ratio, and high drug-loading efficacy. Herein, a number of nanofibrous mats composed of different types of Eudragit® polymers in various concentrations and combinations loaded with furosemide were designed, successfully electrospun, and characterized using SEM, FTIR, DSC, and TGA analyses. The nanofibrous nonwovens were formulated in nanofiber tablets and the release profile of furosemide from them was evaluated at pH 1.2 and 6.8 and compared to that of physical mixture matrix tablets of analogous composition as well as to that of a commercial formulation. It was found that the release of furosemide was compatible with the gastroretentive and slower intestinal release requirements with a well-defined absorption window, while some nanofiber formulations could act as furosemide carriers in emergency situations where a relatively fast onset of its action is required, as in the case of critically ill post-traumatic patients. Full article
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Open AccessArticle
Assessing Drug Interaction and Pharmacokinetics of Loxoprofen in Mice Treated with CYP3A Modulators
Pharmaceutics 2019, 11(9), 479; https://doi.org/10.3390/pharmaceutics11090479 - 16 Sep 2019
Viewed by 447
Abstract
Loxoprofen (LOX) is a non-selective cyclooxygenase inhibitor that is widely used for the treatment of pain and inflammation caused by chronic and transitory conditions. Its alcoholic metabolites are formed by carbonyl reductase (CR) and they consist of trans-LOX, which is active, and cis-LOX, [...] Read more.
Loxoprofen (LOX) is a non-selective cyclooxygenase inhibitor that is widely used for the treatment of pain and inflammation caused by chronic and transitory conditions. Its alcoholic metabolites are formed by carbonyl reductase (CR) and they consist of trans-LOX, which is active, and cis-LOX, which is inactive. In addition, LOX can also be converted into an inactive hydroxylated metabolite (OH-LOXs) by cytochrome P450 (CYP). In a previous study, we reported that CYP3A4 is primarily responsible for the formation of OH-LOX in human liver microsomes. Although metabolism by CYP3A4 does not produce active metabolites, it can affect the conversion of LOX into trans-/cis-LOX, since CYP3A4 activity modulates the substrate LOX concentration. Although the pharmacokinetics (PK) and metabolism of LOX have been well defined, its CYP-related interactions have not been fully characterized. Therefore, we investigated the metabolism of LOX after pretreatment with dexamethasone (DEX) and ketoconazole (KTC), which induce and inhibit the activities of CYP3A, respectively. We monitored their effects on the PK parameters of LOX, cis-LOX, and trans-LOX in mice, and demonstrated that their PK parameters significantly changed in the presence of DEX or KTC pretreatment. Specifically, DEX significantly decreased the concentration of the LOX active metabolite formed by CR, which corresponded to an increased concentration of OH-LOX formed by CYP3A4. The opposite result occurred with KTC (a CYP3A inhibitor) pretreatment. Thus, we conclude that concomitant use of LOX with CYP3A modulators may lead to drug–drug interactions and result in minor to severe toxicity even though there is no direct change in the metabolic pathway that forms the LOX active metabolite. Full article
(This article belongs to the Special Issue Drug–Drug Interactions)
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Open AccessArticle
Therapeutic Effects in a Transient Middle Cerebral Artery Occlusion Rat Model by Nose-To-Brain Delivery of Anti-TNF-Alpha siRNA with Cell-Penetrating Peptide-Modified Polymer Micelles
Pharmaceutics 2019, 11(9), 478; https://doi.org/10.3390/pharmaceutics11090478 - 15 Sep 2019
Viewed by 461
Abstract
We previously reported that siRNA delivery to the brain is improved by the nose-to-brain delivery route and by conjugation with polyethylene glycol-polycaprolactone (PEG-PCL) polymer micelles and the cell-penetrating peptide, Tat (PEG-PCL-Tat). In this study, we evaluated the nose-to-brain delivery of siRNA targeting TNF-α [...] Read more.
We previously reported that siRNA delivery to the brain is improved by the nose-to-brain delivery route and by conjugation with polyethylene glycol-polycaprolactone (PEG-PCL) polymer micelles and the cell-penetrating peptide, Tat (PEG-PCL-Tat). In this study, we evaluated the nose-to-brain delivery of siRNA targeting TNF-α (siTNF-α) conjugated with PEG-PCL-Tat to investigate its therapeutic effects on a transient middle cerebral artery occlusion (t-MCAO) rat model of cerebral ischemia-reperfusion injury. Intranasal treatment was provided 30 min after infarction induced via suturing. Two hours after infarction induction, the suture was removed, and blood flow was released. At 22 h post-reperfusion, we assessed the infarcted area, TNF-α production, and neurological score to determine the therapeutic effects. The infarcted area was observed over a wide range in the untreated group, whereas shrinkage of the infarcted area was observed in rats subjected to intranasal administration of siTNF-α with PEG-PCL-Tat micelles. Moreover, TNF-α production and neurological score in rats treated by intranasal administration of siTNF-α with PEG-PCL-Tat micelles were significantly lower than those in untreated and naked siTNF-α-treated rats. These results indicate that nose-to-brain delivery of siTNF-α conjugated with PEG-PCL-Tat micelles alleviated the symptoms of cerebral ischemia-reperfusion injury. Full article
(This article belongs to the Special Issue Intranasal Drug Delivery Systems)
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Open AccessArticle
Magnetoliposomes Containing Calcium Ferrite Nanoparticles for Applications in Breast Cancer Therapy
Pharmaceutics 2019, 11(9), 477; https://doi.org/10.3390/pharmaceutics11090477 - 14 Sep 2019
Viewed by 436
Abstract
Magnetoliposomes containing calcium ferrite (CaFe2O4) nanoparticles were developed and characterized for the first time. CaFe2O4 nanoparticles were covered by a lipid bilayer or entrapped in liposomes forming, respectively, solid or aqueous magnetoliposomes as nanocarriers for new [...] Read more.
Magnetoliposomes containing calcium ferrite (CaFe2O4) nanoparticles were developed and characterized for the first time. CaFe2O4 nanoparticles were covered by a lipid bilayer or entrapped in liposomes forming, respectively, solid or aqueous magnetoliposomes as nanocarriers for new antitumor drugs. The magnetic nanoparticles were characterized by UV/Visible absorption, XRD, HR-TEM, and SQUID, exhibiting sizes of 5.2 ± 1.2 nm (from TEM) and a superparamagnetic behavior. The magnetoliposomes were characterized by DLS and TEM. The incorporation of two new potential antitumor drugs (thienopyridine derivatives) specifically active against breast cancer in these nanosystems was investigated by fluorescence emission and anisotropy. Aqueous magnetoliposomes, with hydrodynamic diameters around 130 nm, and solid magnetoliposomes with sizes of ca. 170 nm, interact with biomembranes by fusion and are able to transport the antitumor drugs with generally high encapsulation efficiencies (70%). These fully biocompatible drug-loaded magnetoliposomes can be promising as therapeutic agents in future applications of combined breast cancer therapy. Full article
(This article belongs to the Special Issue Novel Anticancer Drug Delivery Systems)
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Open AccessArticle
Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles
Pharmaceutics 2019, 11(9), 476; https://doi.org/10.3390/pharmaceutics11090476 - 14 Sep 2019
Viewed by 396
Abstract
This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a [...] Read more.
This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles. Full article
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Open AccessArticle
Microencapsulation of Enteric Bacteriophages in a pH-Responsive Solid Oral Dosage Formulation Using a Scalable Membrane Emulsification Process
Pharmaceutics 2019, 11(9), 475; https://doi.org/10.3390/pharmaceutics11090475 - 14 Sep 2019
Viewed by 695
Abstract
A scalable low-shear membrane emulsification process was used to produce microencapsulated Escherichia coli-phages in a solid oral dosage form. Uniform pH-responsive composite microparticles (mean size ~100 µm) composed of Eudragit® S100 and alginate were produced. The internal microstructure of the gelled [...] Read more.
A scalable low-shear membrane emulsification process was used to produce microencapsulated Escherichia coli-phages in a solid oral dosage form. Uniform pH-responsive composite microparticles (mean size ~100 µm) composed of Eudragit® S100 and alginate were produced. The internal microstructure of the gelled microcapsules was studied using ion-milling and imaging, which showed that the microparticles had a solid internal core. The microencapsulation process significantly protected phages upon prolonged exposure to a simulated gastric acidic environment. Encapsulated phages that had been pre-exposed to simulated gastric acid were added to actively growing bacterial cells using in vitro cell cultures and were found to be effective in killing E. coli. Encapsulated phages were also shown to be effective in killing actively growing E. coli in the presence of human epithelial cells. Confocal microscopy images showed that the morphology of encapsulated phage-treated epithelial cells was considerably better than controls without phage treatment. The encapsulated phages were stable during refrigerated storage over a four-week period. The process of membrane emulsification is highly scalable and is a promising route to produce industrial quantities of pH-responsive oral solid dosage forms suitable for delivering high titres of viable phages to the gastrointestinal tract. Full article
(This article belongs to the Special Issue Advanced Formulation Approaches for Targeted Drug Delivery)
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Open AccessArticle
A Novel Framework to Aid the Development of Design Space across Multi-Unit Operation Pharmaceutical Processes—A Case Study of Panax Notoginseng Saponins Immediate Release Tablet
Pharmaceutics 2019, 11(9), 474; https://doi.org/10.3390/pharmaceutics11090474 - 13 Sep 2019
Viewed by 353
Abstract
The fundamental principle of Quality by Design (QbD) is that the product quality should be designed into the process through an upstream approach, rather than be tested in the downstream. The keystone of QbD is process modeling, and thus, to develop a process [...] Read more.
The fundamental principle of Quality by Design (QbD) is that the product quality should be designed into the process through an upstream approach, rather than be tested in the downstream. The keystone of QbD is process modeling, and thus, to develop a process control strategy based on the development of design space. Multivariate statistical analysis is a very useful tool to support the implementation of QbD in pharmaceutical process development and manufacturing. Nowadays, pharmaceutical process modeling is mainly focused on one-unit operations and system modeling for the development of design space across multi-unit operations is still limited. In this study, a general procedure that gives a holistic view for understanding and controlling the process settings for the entire manufacturing process was investigated. The proposed framework was tested on the Panax Notoginseng Saponins immediate release tablet (PNS IRT) production process. The critical variables and the critical units acting on the process were identified according to the importance of explaining the variability in the multi-block partial least squares path model. This improved understanding of the process by illustrating how the properties of the raw materials, the process parameters in the wet granulation and the compaction and the intermediate properties affect the tablet properties. Furthermore, the design space was developed to compensate for the variability source from the upstream. The results demonstrated that the proposed framework was an important tool to gain understanding and control the multi-unit operation process. Full article
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Open AccessReview
A Role for Nanoparticles in Treating Traumatic Brain Injury
Pharmaceutics 2019, 11(9), 473; https://doi.org/10.3390/pharmaceutics11090473 - 13 Sep 2019
Viewed by 501
Abstract
Traumatic brain injury (TBI) is one of the main causes of disability in children and young adults, as well as a significant concern for elderly individuals. Depending on the severity, TBI can have a long-term impact on the quality of life for survivors [...] Read more.
Traumatic brain injury (TBI) is one of the main causes of disability in children and young adults, as well as a significant concern for elderly individuals. Depending on the severity, TBI can have a long-term impact on the quality of life for survivors of all ages. The primary brain injury can result in severe disability or fatality, and secondary brain damage can increase the complexities in cellular, inflammatory, neurochemical, and metabolic changes in the brain, which can last decades post-injury. Thus, survival from a TBI is often accompanied by lifelong disabilities. Despite the significant morbidity, mortality, and economic loss, there are still no effective treatment options demonstrating an improved outcome in a large multi-center Phase III trial, which can be partially attributed to poor target engagement of delivered therapeutics. Thus, there is a significant unmet need to develop more effective delivery strategies to overcome the biological barriers that would otherwise inhibit transport of materials into the brain to prevent the secondary long-term damage associated with TBI. The complex pathology of TBI involving the blood-brain barrier (BBB) has limited the development of effective therapeutics and diagnostics. Therefore, it is of great importance to develop novel strategies to target the BBB. The leaky BBB caused by a TBI may provide opportunities for therapeutic delivery via nanoparticles (NP). The focus of this review is to provide a survey of NP-based strategies employed in preclinical models of TBI and to provide insights for improved NP based diagnostic or treatment approaches. Both passive and active delivery of various NPs for TBI are discussed. Finally, potential therapeutic targets where improved NP-mediated delivery could increase target engagement are identified with the overall goal of providing insight into open opportunities for NP researchers to begin research in TBI. Full article
(This article belongs to the Special Issue Molecular Imaging in Targeted Drug Delivery)
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Open AccessReview
Norovirus Capsid Protein-Derived Nanoparticles and Polymers as Versatile Platforms for Antigen Presentation and Vaccine Development
Pharmaceutics 2019, 11(9), 472; https://doi.org/10.3390/pharmaceutics11090472 - 12 Sep 2019
Viewed by 486
Abstract
Major viral structural proteins interact homotypically and/or heterotypically, self-assembling into polyvalent viral capsids that usually elicit strong host immune responses. By taking advantage of such intrinsic features of norovirus capsids, two subviral nanoparticles, 60-valent S60 and 24-valent P24 nanoparticles, as well [...] Read more.
Major viral structural proteins interact homotypically and/or heterotypically, self-assembling into polyvalent viral capsids that usually elicit strong host immune responses. By taking advantage of such intrinsic features of norovirus capsids, two subviral nanoparticles, 60-valent S60 and 24-valent P24 nanoparticles, as well as various polymers, have been generated through bioengineering norovirus capsid shell (S) and protruding (P) domains, respectively. These nanoparticles and polymers are easily produced, highly stable, and extremely immunogenic, making them ideal vaccine candidates against noroviruses. In addition, they serve as multifunctional platforms to display foreign antigens, self-assembling into chimeric nanoparticles or polymers as vaccines against different pathogens and illnesses. Several chimeric S60 and P24 nanoparticles, as well as P domain-derived polymers, carrying different foreign antigens, have been created and demonstrated to be promising vaccine candidates against corresponding pathogens in preclinical animal studies, warranting their further development into useful vaccines. Full article
(This article belongs to the Special Issue Nanoparticles to Improve the Efficacy of Vaccines)
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Open AccessReview
Fluorescence Imaging as a Tool in Preclinical Evaluation of Polymer-Based Nano-DDS Systems Intended for Cancer Treatment
Pharmaceutics 2019, 11(9), 471; https://doi.org/10.3390/pharmaceutics11090471 - 12 Sep 2019
Viewed by 398
Abstract
Targeted drug delivery using nano-sized carrier systems with targeting functions to malignant and inflammatory tissue and tailored controlled drug release inside targeted tissues or cells has been and is still intensively studied. A detailed understanding of the correlation between the pharmacokinetic properties and [...] Read more.
Targeted drug delivery using nano-sized carrier systems with targeting functions to malignant and inflammatory tissue and tailored controlled drug release inside targeted tissues or cells has been and is still intensively studied. A detailed understanding of the correlation between the pharmacokinetic properties and structure of the nano-sized carrier is crucial for the successful transition of targeted drug delivery nanomedicines into clinical practice. In preclinical research in particular, fluorescence imaging has become one of the most commonly used powerful imaging tools. Increasing numbers of suitable fluorescent dyes that are excitable in the visible to near-infrared (NIR) wavelengths of the spectrum and the non-invasive nature of the method have significantly expanded the applicability of fluorescence imaging. This chapter summarizes non-invasive fluorescence-based imaging methods and discusses their potential advantages and limitations in the field of drug delivery, especially in anticancer therapy. This chapter focuses on fluorescent imaging from the cellular level up to the highly sophisticated three-dimensional imaging modality at a systemic level. Moreover, we describe the possibility for simultaneous treatment and imaging using fluorescence theranostics and the combination of different imaging techniques, e.g., fluorescence imaging with computed tomography. Full article
(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)
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Open AccessArticle
Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against Hypermutable Pseudomonas Aeruginosa Strains via Mechanism-Based Modelling
Pharmaceutics 2019, 11(9), 470; https://doi.org/10.3390/pharmaceutics11090470 - 12 Sep 2019
Viewed by 383
Abstract
Hypermutable Pseudomonas aeruginosa strains have a greatly increased mutation rate and are prevalent in chronic respiratory infections. Initially, we systematically evaluated the time-course of total and resistant populations of hypermutable (PAO∆mutS) and non-hypermutable (PAO1) P. aeruginosa strains in 48-h static concentration [...] Read more.
Hypermutable Pseudomonas aeruginosa strains have a greatly increased mutation rate and are prevalent in chronic respiratory infections. Initially, we systematically evaluated the time-course of total and resistant populations of hypermutable (PAO∆mutS) and non-hypermutable (PAO1) P. aeruginosa strains in 48-h static concentration time-kill studies with two inocula. Both strains were exposed to clinically relevant concentrations of important antibiotics (aztreonam, ceftazidime, imipenem, meropenem, tobramycin, and ciprofloxacin) in monotherapy. The combination of tobramycin and ciprofloxacin was subsequently assessed in 48-h static concentration time-kill studies against PAO1, PAO∆mutS, and two hypermutable clinical P. aeruginosa strains. Mechanism-based mathematical modelling was conducted to describe the time-course of total and resistant bacteria for all four strains exposed to the combination. With all monotherapies, bacterial regrowth and resistant populations were overall more pronounced for PAO∆mutS compared to PAO1. The combination of tobramycin and ciprofloxacin was synergistic, with up to 106.1 colony forming units (CFU)/mL more bacterial killing than the most active monotherapy for all strains, and largely suppressed less-susceptible populations. This work indicates that monotherapies against hypermutable P. aeruginosa strains are not a viable option. Tobramycin with ciprofloxacin was identified as a promising and tangible option to combat hypermutable P. aeruginosa strains. Full article
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Open AccessArticle
Development and Evaluation of Multifunctional Poly(Lactic-co-glycolic acid) Nanoparticles Embedded in Carboxymethyl β-Glucan Porous Microcapsules as a Novel Drug Delivery System for Gefitinib
Pharmaceutics 2019, 11(9), 469; https://doi.org/10.3390/pharmaceutics11090469 - 12 Sep 2019
Viewed by 392
Abstract
In this study, a new kind of folic acid (FA)-conjugated and chitosan (CS)-coated poloxamer 407 (P407)/poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), FCPP NPs, were prepared, and further micro-encapsulated by carboxymethyl β-glucan microcapsules (MCs) to produce a multifunctional system of NPs embedded in [...] Read more.
In this study, a new kind of folic acid (FA)-conjugated and chitosan (CS)-coated poloxamer 407 (P407)/poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), FCPP NPs, were prepared, and further micro-encapsulated by carboxymethyl β-glucan microcapsules (MCs) to produce a multifunctional system of NPs embedded in MCs (NEMs) for potential lung tumor-targeted delivery of gefitinib. The prepared gefitinib-loaded FCPP (GFB/FCPP) NPs showed a hydrodynamic diameter of 255.4 ± 14.5 nm and existed in an amorphous state. After encapsulation in carboxymethyl β-glucan MCs, the GFB/FCPP-based NEMs (GFB/FCPP-NEMs) also exhibited a spherical morphology with a median diameter (d50) of around 2.2 μm. After hydration, GFB/FCPP- NEMs can quickly dissociate into its primary particles, GFB/FCPP NPs. Our in vitro drug release study revealed that these GFB/FCPP-NEMs exhibited a pH-responsive prolonged release property. In addition, the cellular uptake study demonstrated that FCPP-NEMs serve as an efficient carrier to enhance the delivery of the entrapped drug into the target lung tumor cells. Moreover, the GFB/FCPP-NEMs induced a superior cytotoxic effect compared with free gefitinib. The inhibitory concentration to achieve 50% cell death (IC50) of GFB/FCPP-NEMs in A549 cells was 3.82-fold lower than that of free gefitinib. According to these results, FCPP-NEMs hold a great potential as a multifunctional and high-performance biomaterial for lung tumor targeting delivery, pH-responsive sustained release, facilitated cellular uptake, and enhanced antitumor effect of antitumor drugs, like gefitinib. Full article
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Open AccessArticle
A Valid Bisphosphonate Modified Calcium Phosphate-Based Gene Delivery System: Increased Stability and Enhanced Transfection Efficiency In Vitro and In Vivo
Pharmaceutics 2019, 11(9), 468; https://doi.org/10.3390/pharmaceutics11090468 - 11 Sep 2019
Viewed by 465
Abstract
Calcium phosphate (CaP) nanoparticles, as a promising vehicle for gene delivery, have been widely used owing to their biocompatibility, biodegradability and adsorptive capacity for nucleic acids. Unfortunately, their utility in vivo has been profoundly restricted due to numerous technical barriers such as the [...] Read more.
Calcium phosphate (CaP) nanoparticles, as a promising vehicle for gene delivery, have been widely used owing to their biocompatibility, biodegradability and adsorptive capacity for nucleic acids. Unfortunately, their utility in vivo has been profoundly restricted due to numerous technical barriers such as the lack of tissue specificity and limited transfection efficiency, as well as uncontrollable aggregation over time. To address these issues, an effective conjugate folate-polyethylene glycol-pamidronate (shortened as FA-PEG-Pam) was designed and coated on the surface of CaP/NLS/pDNA (CaP/NDs), forming a versatile gene carrier FA-PEG-Pam/CaP/NDs. Inclusion of FA-PEG-Pam significantly reduced the size of CaP nanoparticles, thus inhibiting the aggregation of CaP nanoparticles. FA-PEG-Pam/CaP/NDs showed better cellular uptake than mPEG-Pam/CaP/NDs, which could be attributed to the high-affinity interactions between FA and highly expressed FR. Meanwhile, FA-PEG-Pam/CaP/NDs had low cytotoxicity and desired effect on inducing apoptosis (71.1%). Furthermore, FA-PEG-Pam/CaP/NDs showed admirable transfection efficiency (63.5%) due to the presence of NLS peptides. What’s more, in vivo studies revealed that the hybrid nanoparticles had supreme antitumor activity (IR% = 58.7%) among the whole preparations. Altogether, FA-PEG-Pam/CaP/NDs was expected to be a hopeful strategy for gene delivery. Full article
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Open AccessArticle
Brain Delivery of a Potent Opioid Receptor Agonist, Biphalin during Ischemic Stroke: Role of Organic Anion Transporting Polypeptide (OATP)
Pharmaceutics 2019, 11(9), 467; https://doi.org/10.3390/pharmaceutics11090467 - 10 Sep 2019
Viewed by 467
Abstract
Transporters (expressed) at the blood-brain barrier (BBB) can play an essential role in the treatment of brain injury by transporting neuroprotective substance to the central nervous system. The goal of this study was to understand the role of organic anion transporting polypeptide (OATP1; [...] Read more.
Transporters (expressed) at the blood-brain barrier (BBB) can play an essential role in the treatment of brain injury by transporting neuroprotective substance to the central nervous system. The goal of this study was to understand the role of organic anion transporting polypeptide (OATP1; OATP1A2 in humans and oatp1a4 in rodents) in the transport of a potent opioid receptor agonist, biphalin, across the BBB during ischemic stroke. Brain microvascular endothelial cells (BMECs) that were differentiated from human induced pluripotent stem cells (iPSCs) were used in the present study. The effect of oxygen-glucose deprivation (OGD) and reperfusion on the OATP1 expression, uptake, and transport of biphalin was measured in induced pluripotent stem cells differentiated brain microvascular endothelial cells (iPSC–BMECs) in the presence and absence of an OATP1 substrate, estrone-3-sulfate (E3S). Biphalin brain permeability was quantified while using a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. It was found that iPSC-BMECs expressed OATP1. In vitro studies showed that biphalin BBB uptake and transport decreased in the presence of an OATP1 specific substrate. It was also observed that OGD and reperfusion modulate the expression and function of OATP1 in BMECs. This study strongly demonstrates that OATP1 contributes to the transport of biphalin across the BBB and increased expression of OATP1 during OGD-reperfusion could provide a novel target for improving ischemic brain drug delivery of biphalin or other potential neurotherapeutics that have affinity to this BBB transporter. Full article
(This article belongs to the Special Issue Drug Delivery to the Brain)
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Open AccessArticle
A Multi-Label Learning Framework for Drug Repurposing
Pharmaceutics 2019, 11(9), 466; https://doi.org/10.3390/pharmaceutics11090466 - 09 Sep 2019
Viewed by 415
Abstract
Drug repurposing plays an important role in screening old drugs for new therapeutic efficacy. The existing methods commonly treat prediction of drug-target interaction as a problem of binary classification, in which a large number of randomly sampled drug-target pairs accounting for over 50% [...] Read more.
Drug repurposing plays an important role in screening old drugs for new therapeutic efficacy. The existing methods commonly treat prediction of drug-target interaction as a problem of binary classification, in which a large number of randomly sampled drug-target pairs accounting for over 50% of the entire training dataset are necessarily required. Such a large number of negative examples that do not come from experimental observations inevitably decrease the credibility of predictions. In this study, we propose a multi-label learning framework to find new uses for old drugs and discover new drugs for known target genes. In the framework, each drug is treated as a class label and its target genes are treated as the class-specific training data to train a supervised learning model of l2-regularized logistic regression. As such, the inter-drug associations are explicitly modelled into the framework and all the class-specific training data come from experimental observations. In addition, the data constraint is less demanding, for instance, the chemical substructures of a drug are no longer needed and the novel target genes are inferred only from the underlying patterns of the known genes targeted by the drug. Stratified multi-label cross-validation shows that 84.9% of known target genes have at least one drug correctly recognized, and the proposed framework correctly recognizes 86.73% of the independent test drug-target interactions (DTIs) from DrugBank. These results show that the proposed framework could generalize well in the large drug/class space without the information of drug chemical structures and target protein structures. Furthermore, we use the trained model to predict new drugs for the known target genes, identify new genes for the old drugs, and infer new associations between old drugs and new disease phenotypes via the OMIM database. Gene ontology (GO) enrichment analyses and the disease associations reported in recent literature provide supporting evidences to the computational results, which potentially shed light on new clinical therapies for new and/or old disease phenotypes. Full article
(This article belongs to the Special Issue Computational Drug Repurposing)
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Open AccessReview
Development and Characterization of the Solvent-Assisted Active Loading Technology (SALT) for Liposomal Loading of Poorly Water-Soluble Compounds
Pharmaceutics 2019, 11(9), 465; https://doi.org/10.3390/pharmaceutics11090465 - 09 Sep 2019
Viewed by 436
Abstract
A large proportion of pharmaceutical compounds exhibit poor water solubility, impacting their delivery. These compounds can be passively encapsulated in the lipid bilayer of liposomes to improve their water solubility, but the loading capacity and stability are poor, leading to burst drug leakage. [...] Read more.
A large proportion of pharmaceutical compounds exhibit poor water solubility, impacting their delivery. These compounds can be passively encapsulated in the lipid bilayer of liposomes to improve their water solubility, but the loading capacity and stability are poor, leading to burst drug leakage. The solvent-assisted active loading technology (SALT) was developed to promote active loading of poorly soluble drugs in the liposomal core to improve the encapsulation efficiency and formulation stability. By adding a small volume (~5 vol%) of a water miscible solvent to the liposomal loading mixture, we achieved complete, rapid loading of a range of poorly soluble compounds and attained a high drug-to-lipid ratio with stable drug retention. This led to improvements in the circulation half-life, tolerability, and efficacy profiles. In this mini-review, we summarize our results from three studies demonstrating that SALT is a robust and versatile platform to improve active loading of poorly water-soluble compounds. We have validated SALT as a tool for improving drug solubility, liposomal loading efficiency and retention, stability, palatability, and pharmacokinetics (PK), while retaining the ability of the compounds to exert pharmacological effects. Full article
(This article belongs to the Special Issue Drug Delivery Technology Development in Canada)
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Open AccessArticle
Comprehensive Analysis of the Safety Profile of a Single-Stranded RNA Nano-Structure Adjuvant
Pharmaceutics 2019, 11(9), 464; https://doi.org/10.3390/pharmaceutics11090464 - 07 Sep 2019
Viewed by 442
Abstract
Adjuvants enhance the efficacy of vaccines by stimulating immune response-related gene expression and pathways. Although some adjuvants have been approved for commercial use in human vaccines (e.g., Alum, MF59, and AS03), they might elicit adverse side effects, such as autoimmune diseases. Recently, we [...] Read more.
Adjuvants enhance the efficacy of vaccines by stimulating immune response-related gene expression and pathways. Although some adjuvants have been approved for commercial use in human vaccines (e.g., Alum, MF59, and AS03), they might elicit adverse side effects, such as autoimmune diseases. Recently, we developed a novel single-stranded RNA (ssRNA) nano-structure adjuvant, which can stimulate both Th1 and Th2 responses. In this study, we evaluated the safety and toxicological profiles of this ssRNA nano-structure adjuvant in vitro and in vivo. Mice were intramuscularly immunized with the ssRNA nano-structure adjuvant three times, once every 2 weeks. The results indicate no significant differences in hematological and serum biochemistry parameters between the ssRNA-treated groups and the control group. From a histopathological perspective, no evidence of tissue damage was found in any group. The levels of IgE and anti-nuclear antibodies, which are markers of autoimmune disease, were not different between the ssRNA-treated groups and the control group. The findings of this study suggest that the ssRNA nano-structure can be used as a safe adjuvant to increase vaccine efficacies. Full article
(This article belongs to the Special Issue Nanoparticles to Improve the Efficacy of Vaccines)
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Open AccessArticle
Metal–Organic Framework-Based Chemo-Photothermal Combinational System for Precise, Rapid, and Efficient Antibacterial Therapeutics
Pharmaceutics 2019, 11(9), 463; https://doi.org/10.3390/pharmaceutics11090463 - 06 Sep 2019
Viewed by 456
Abstract
Rapid increase of antimicrobial resistance has become an urgent threat to global public health. In this research, since photothermal therapy is a potential antibacterial strategy, which is less likely to cause resistance, a metal–organic framework-based chemo-photothermal combinational system was constructed. Zeolitic imidazolate frameworks-8 [...] Read more.
Rapid increase of antimicrobial resistance has become an urgent threat to global public health. In this research, since photothermal therapy is a potential antibacterial strategy, which is less likely to cause resistance, a metal–organic framework-based chemo-photothermal combinational system was constructed. Zeolitic imidazolate frameworks-8 (ZIF-8), a porous carrier with unique features such as high loading and pH-sensitive degradation, was synthesized, and then encapsulated photothermal agent indocyanine green (ICG). First, ICG with improved stability in ZIF-8 (ZIF-8-ICG) can effectively produce heat in response to NIR laser irradiation for precise, rapid, and efficient photothermal bacterial ablation. Meanwhile, Zn2+ ions released from ZIF-8 can inhibit bacterial growth by increasing the permeability of bacterial cell membrane and further strengthen photothermal therapy efficacy by reducing the heat resistance of bacteria. Study showed that bacteria suffered from significant changes in morphology after treatment with ZIF-8-ICG under laser irradiation. The combinational chemo-hyperthermia therapy of ZIF-8-ICG could thoroughly ablate murine subcutaneous abscess induced by methicillin-resistant Staphylococcus aureus (MRSA), exhibiting a nearly 100% bactericidal ratio. Both in vitro and in vivo safety evaluation confirmed that ZIF-8-ICG was low toxic. Overall, our researches demonstrated that ZIF-8-ICG has great potential to be served as an alternative to antibiotics in combating multidrug-resistant bacterial pathogens. Full article
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Open AccessArticle
Oxidation- and Temperature-Responsive Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) Micelle as a Potential Anticancer Drug Carrier
Pharmaceutics 2019, 11(9), 462; https://doi.org/10.3390/pharmaceutics11090462 - 06 Sep 2019
Viewed by 402
Abstract
Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) (P(HEA-co-PVS)), as an oxidizable amphiphilic polymer, was prepared for the fabrication of an oxidation- and temperature-responsive micelle for the delivery of doxorubicin (DOX). The interfacial activity of H2O2-treated P(HEA-co-PVS) [...] Read more.
Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) (P(HEA-co-PVS)), as an oxidizable amphiphilic polymer, was prepared for the fabrication of an oxidation- and temperature-responsive micelle for the delivery of doxorubicin (DOX). The interfacial activity of H2O2-treated P(HEA-co-PVS) was significantly lower than that of the untreated variety, possibly because of the oxidization of PVS. P(HEA-co-PVS) exhibited a lower critical solution temperature (LCST) behavior and the LCST increased upon H2O2 treatment. The copolymer micelles, prepared by the dialysis method, were found to be round particles (less than 100 nm) on TEM micrograph. The release degree of Nile red loaded in the micelles was higher when the H2O2 concentration was higher, possibly because the micelles could be solubilized more readily at a higher H2O2 concentration. The release degree was more strongly dependent on the oxidizing agent concentration when the temperature was higher. DOX loaded in the micelles suppressed the in vitro growth of KB cells (a human cancer cell type originating from the cervix) much more effectively than DOX loaded in an unoxidizable control micelle and free DOX, possibly because the copolymer would undergo an increase in its LCST, lose its amphiphilic property, and the micelles would be disassembled. The DOX-loaded micelles were readily internalized into KB cells, as evidenced by flow cytometry (FACS) and confocal laser scanning microscopy (CLSM). Full article
(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)
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Open AccessArticle
Spray-Dried Amorphous Solid Dispersions of Atorvastatin Calcium for Improved Supersaturation and Oral Bioavailability
Pharmaceutics 2019, 11(9), 461; https://doi.org/10.3390/pharmaceutics11090461 - 06 Sep 2019
Viewed by 546
Abstract
Over the past few decades, the amorphous solid dispersions (ASDs) technique has emerged as a promising strategy to enhance the in vitro/in vivo characteristic of hydrophobic drugs. The low aqueous solubility and poor bioavailability of atorvastatin calcium (ATO), a lipid-lowering drug, present challenges [...] Read more.
Over the past few decades, the amorphous solid dispersions (ASDs) technique has emerged as a promising strategy to enhance the in vitro/in vivo characteristic of hydrophobic drugs. The low aqueous solubility and poor bioavailability of atorvastatin calcium (ATO), a lipid-lowering drug, present challenges for effective drug delivery. The objective of this work was to improve the aqueous solubility, in vitro dissolution, and oral absorption of ATO with amorphous solid dispersion technique prepared by spray-drying method. The optimized ternary formulation comprising of ATO; hydroxypropyl methylcellulose (HPMC), as a hydrophilic polymer; and sodium lauryl sulfate (SLS), as a surfactant, at a weight ratio of 1/1/0.1, showed significant improvement in aqueous solubility by ~18-fold compared to that of the free drug, and a cumulative release of 94.09% compared to a release of 59.32% of the free drug. Further, physicochemical studies via scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction revealed a change from the crystalline state of the free drug to its amorphous state in the ASD. Pharmacokinetic analysis in rats demonstrated 1.68- and 2.39-fold increments in AUC and Cmax, respectively, in the ASD over the free drug. Altogether, hydrophilic carrier-based ASDs prepared by the spray-drying technique represent a promising strategy to improve the biopharmaceutical performance of poorly soluble drugs. Full article
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Open AccessReview
Advanced Formulation Approaches for Ocular Drug Delivery: State-Of-The-Art and Recent Patents
Pharmaceutics 2019, 11(9), 460; https://doi.org/10.3390/pharmaceutics11090460 - 06 Sep 2019
Viewed by 560
Abstract
The eye presents extensive perspectives and challenges for drug delivery, mainly because of the extraordinary capacity, intrinsic to this path, for drugs to permeate into the main circulatory system and also for the restrictions of the ocular barriers. Depending on the target segment [...] Read more.
The eye presents extensive perspectives and challenges for drug delivery, mainly because of the extraordinary capacity, intrinsic to this path, for drugs to permeate into the main circulatory system and also for the restrictions of the ocular barriers. Depending on the target segment of the eye, anterior or posterior, the specifications are different. The ocular route experienced in the last decades a lot of progresses related with the development of new drugs, improved formulations, specific-designed delivery and even new routes to administer a drug. Concomitantly, new categories of materials were developed and adapted to encapsulate drugs. With such advances, a multiplicity of parameters became possible to be optimized as the increase in bioavailability and decreased toxic effects of medicines. Also, the formulations were capable to easily adhere to specific tissues, increase the duration of the therapeutic effect and even target the delivery of the treatment. The ascending of new delivery systems for ocular targeting is a current focus, mainly because of the capacity to extend the normal time during which the drug exerts its therapeutic effect and, so, supplying the patients with a product which gives them fewer side effects, fewer number of applications and even more effective outcomes to their pathologies, surpassing the traditionally-used eye drops. Depending on the systems, some are capable of increasing the duration of the drug action as gels, emulsions, prodrugs, liposomes, and ocular inserts with hydrophilic properties, improving the absorption by the cornea. In parallel, other devices use as a strategy the capacity to sustain the release of the carried drugs by means of erodible and non-erodible matrices. This review discusses the different types of advanced formulations used for ocular delivery of therapeutics presenting the most recent patents according to the clinical applications. Full article
(This article belongs to the Special Issue Advanced Formulation Approaches for Targeted Drug Delivery)
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Open AccessArticle
Size Distribution of Colistin Delivery by Different Type Nebulizers and Concentrations During Mechanical Ventilation
Pharmaceutics 2019, 11(9), 459; https://doi.org/10.3390/pharmaceutics11090459 - 05 Sep 2019
Viewed by 544
Abstract
Although aerosol delivery through mechanical ventilators has been used to administer various medications, little is known of administration with colistin. This in vitro evaluation aimed to evaluate size distribution of colistin delivery by different types of nebulizers and concentrations during mechanical ventilation. Colistin [...] Read more.
Although aerosol delivery through mechanical ventilators has been used to administer various medications, little is known of administration with colistin. This in vitro evaluation aimed to evaluate size distribution of colistin delivery by different types of nebulizers and concentrations during mechanical ventilation. Colistin methanesulfonate (colistin) for injection was dissolved in 6 mL of distilled water to produce a low concentration (L; 156 mg) and a high concentration (H; 312 mg). A dose volume of 6 mL was placed in a vibrating mesh nebulizer (VMN) and a jet nebulizer (JN). The inhaled mass (mean ± SD) of the VMN-L (53.80 ± 14.79 mg) was greater than both the JN-L (19.82 ± 3.34 mg, P = 0.001) and JN-H (31.72 ± 4.48 mg, P = 0.017). The nebulization time of the VMN-L (42.35 ± 2.30 min) was two times longer than the JN-L (21.12 ± 0.8 min) or JN-H (21.65 ± 0.42 min; P < 0.001). The mass median aerodynamic distal to the endotracheal tube was within a similar range at 2.03 to 2.26 μm (P = 0.434), independent of neb or formulation concentration. In conclusion, the VMN-L yields greater inhaled mass than the JN with either concentration. Therefore, a standard nominal dose of colistin results in a higher delivered dose during mechanical ventilation with a VMN compared with a JN and may be considered the preferred device. If JN must be used, multiple doses of low concentration colistin may compensate for poor delivery performance. Full article
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Open AccessArticle
Intracellular Delivery of siRNAs Targeting AKT and ERBB2 Genes Enhances Chemosensitization of Breast Cancer Cells in a Culture and Animal Model
Pharmaceutics 2019, 11(9), 458; https://doi.org/10.3390/pharmaceutics11090458 - 03 Sep 2019
Viewed by 544
Abstract
Pharmacotherapy as the mainstay in the management of breast cancer suffers from various drawbacks, including non-targeted biodistribution, narrow therapeutic and safety windows, and also resistance to treatment. Thus, alleviation of the constraints from the pharmacodynamic and pharmacokinetic profile of classical anti-cancer drugs could [...] Read more.
Pharmacotherapy as the mainstay in the management of breast cancer suffers from various drawbacks, including non-targeted biodistribution, narrow therapeutic and safety windows, and also resistance to treatment. Thus, alleviation of the constraints from the pharmacodynamic and pharmacokinetic profile of classical anti-cancer drugs could lead to improvements in efficacy and patient survival in malignancies. Moreover, modifications in the genetic pathophysiology of cancer via administration of small nucleic acids might pave the way towards higher response rates to chemotherapeutics. Inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized in this study to efficiently deliver various classes of therapeutics into cancer cells. Co-delivery of drugs and genetic materials was successfully attained through a carbonate apatite delivery device. On 4T1 cells, siRNAs against AKT and ERBB2 plus paclitaxel or docetaxel resulted in the largest increase in anti-cancer effects compared to CA/paclitaxel or CA/docetaxel. Therefore, these ingredients were selected for further in vivo investigations. Animals receiving injections of CA/paclitaxel or CA/docetaxel loaded with siRNAs against AKT and ERBB2 possessed significantly smaller tumors compared to CA/drug-treated mice. Interestingly, synergistic interactions in target protein knock down with combinations of CA/AKT/paclitaxel, CA/ERBB2/docetaxel were documented via western blotting. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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