Pharmaceutics

21 pages, 3343 KiB

Open AccessArticle

The Physicochemical, Biopharmaceutical, and In Vitro Efficacy Properties of Freeze-Dried Dexamethasone-Loaded Lipomers

by Eloy Pena-Rodríguez, Aida Mata-Ventosa, Laura Garcia-Vega, Sandra Pérez-Torras and Francisco Fernández-Campos

Pharmaceutics 2021, 13(8), 1322; https://doi.org/10.3390/pharmaceutics13081322 - 23 Aug 2021

Cited by 7 | Viewed by 3965

Abstract

Dexamethasone-loaded polymer hybrid nanoparticles were developed as a potential tool to treat alopecia areata due to their follicular targeting ability. Freeze drying (FD) is a common technique used to improve nanoparticle stability; however, there are few studies focused on its effect on ethyl [...] Read more.

Dexamethasone-loaded polymer hybrid nanoparticles were developed as a potential tool to treat alopecia areata due to their follicular targeting ability. Freeze drying (FD) is a common technique used to improve nanoparticle stability; however, there are few studies focused on its effect on ethyl cellulose lipid-core nanoparticles. Nanoparticles were lyophilized with different cryoprotectants. Sucrose was selected because it allowed for a good resuspension and provided acceptable physicochemical parameters (374.33 nm, +34.7 mV, polydispersion 0.229%, and 98.87% encapsulation efficiency). The nanoparticles obtained were loaded into a pleasant xanthan gum hydrogel, and the rheological, release, and skin permeation profiles of different formulations were studied. The FD formulation significantly modified the particle size, and the drug release and permeation properties were also altered. In addition, analyses of the cytotoxicity and anti-inflammatory efficacy of FD and non-FD particles on human keratinocytes indicated no differences. Full article

(This article belongs to the Special Issue Drug Delivery and Penetration through Skin and Its Formulations)

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27 pages, 2168 KiB

Open AccessReview

Nanocarriers as a Tool for the Treatment of Colorectal Cancer

by Ana Luiza C. de S. L. Oliveira, Timo Schomann, Lioe-Fee de Geus-Oei, Ellen Kapiteijn, Luis J. Cruz and Raimundo Fernandes de Araújo Junior

Pharmaceutics 2021, 13(8), 1321; https://doi.org/10.3390/pharmaceutics13081321 - 23 Aug 2021

Cited by 13 | Viewed by 4782

Abstract

Nanotechnology is a promising tool for the treatment of cancer. In the past decades, major steps have been made to bring nanotechnology into the clinic in the form of nanoparticle-based drug delivery systems. The great hope of drug delivery systems is to reduce [...] Read more.

Nanotechnology is a promising tool for the treatment of cancer. In the past decades, major steps have been made to bring nanotechnology into the clinic in the form of nanoparticle-based drug delivery systems. The great hope of drug delivery systems is to reduce the side effects of chemotherapeutics while simultaneously increasing the efficiency of the therapy. An increased treatment efficiency would greatly benefit the quality of life as well as the life expectancy of cancer patients. However, besides its many advantages, nanomedicines have to face several challenges and hurdles before they can be used for the effective treatment of tumors. Here, we give an overview of the hallmarks of cancer, especially colorectal cancer, and discuss biological barriers as well as how drug delivery systems can be utilized for the effective treatment of tumors and metastases. Full article

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

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22 pages, 1584 KiB

Open AccessReview

Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy

by Rafael Simó, Olga Simó-Servat, Patricia Bogdanov and Cristina Hernández

Pharmaceutics 2021, 13(8), 1320; https://doi.org/10.3390/pharmaceutics13081320 - 23 Aug 2021

Cited by 39 | Viewed by 5058

Abstract

The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages [...] Read more.

The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice. Full article

(This article belongs to the Special Issue Current and Future Treatments for Diabetic Retinopathy)

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16 pages, 4310 KiB

Open AccessArticle

Stimuli-Responsive Nanofibers Containing Gold Nanorods for On-Demand Drug Delivery Platforms

by Baljinder Singh, Nutan Shukla, Junkee Kim, Kibeom Kim and Myoung-Hwan Park

Pharmaceutics 2021, 13(8), 1319; https://doi.org/10.3390/pharmaceutics13081319 - 23 Aug 2021

Cited by 33 | Viewed by 4311

Abstract

On-demand drug delivery systems using nanofibers have attracted significant attention owing to their controllable properties for drug release through external stimuli. Near-infrared (NIR)-responsive nanofibers provide a platform where the drug release profile can be achieved by the on-demand supply of drugs at a [...] Read more.

On-demand drug delivery systems using nanofibers have attracted significant attention owing to their controllable properties for drug release through external stimuli. Near-infrared (NIR)-responsive nanofibers provide a platform where the drug release profile can be achieved by the on-demand supply of drugs at a desired dose for cancer therapy. Nanomaterials such as gold nanorods (GNRs) exhibit absorbance in the NIR range, and in response to NIR irradiation, they generate heat as a result of a plasmon resonance effect. In this study, we designed poly (N-isopropylacrylamide) (PNIPAM) composite nanofibers containing GNRs. PNIPAM is a heat-reactive polymer that provides a swelling and deswelling property to the nanofibers. Electrospun nanofibers have a large surface-area-to-volume ratio, which is used to effectively deliver large quantities of drugs. In this platform, both hydrophilic and hydrophobic drugs can be introduced and manipulated. On-demand drug delivery systems were obtained through stimuli-responsive nanofibers containing GNRs and PNIPAM. Upon NIR irradiation, the heat generated by the GNRs ensures shrinking of the nanofibers owing to the thermal response of PNIPAM, thereby resulting in a controlled drug release. The versatility of the light-responsive nanofibers as a drug delivery platform was confirmed in cell studies, indicating the advantages of the swelling and deswelling property of the nanofibers and on–off drug release behavior with good biocompatibility. In addition, the system has potential for the combination of chemotherapy with multiple drugs to enhance the effectiveness of complex cancer treatments. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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21 pages, 848 KiB

Open AccessReview

Recent Technologies for Amorphization of Poorly Water-Soluble Drugs

by Dohyun Kim, Youngwoo Kim, Yee-Yee Tin, Mya-Thet-Paing Soe, Byounghyen Ko, Sunjae Park and Jaehwi Lee

Pharmaceutics 2021, 13(8), 1318; https://doi.org/10.3390/pharmaceutics13081318 - 23 Aug 2021

Cited by 43 | Viewed by 5980

Abstract

Amorphization technology has been the subject of continuous attention in the pharmaceutical industry, as a means to enhance the solubility of poorly water-soluble drugs. Being in a high energy state, amorphous formulations generally display significantly increased apparent solubility as compared to their crystalline [...] Read more.

Amorphization technology has been the subject of continuous attention in the pharmaceutical industry, as a means to enhance the solubility of poorly water-soluble drugs. Being in a high energy state, amorphous formulations generally display significantly increased apparent solubility as compared to their crystalline counterparts, which may allow them to generate a supersaturated state in the gastrointestinal tract and in turn, improve the bioavailability. Conventionally, hydrophilic polymers have been used as carriers, in which the amorphous drugs were dispersed and stabilized to form polymeric amorphous solid dispersions. However, the technique had its limitations, some of which include the need for a large number of carriers, the tendency to recrystallize during storage, and the possibility of thermal decomposition of the drug during preparation. Therefore, emerging amorphization technologies have focused on the investigation of novel amorphous-stabilizing carriers and preparation methods that can improve the drug loading and the degree of amorphization. This review highlights the recent pharmaceutical approaches utilizing drug amorphization, such as co-amorphous systems, mesoporous particle-based techniques, and in situ amorphization. Recent updates on these technologies in the last five years are discussed with a focus on their characteristics and commercial potential. Full article

(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)

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22 pages, 959 KiB

Open AccessReview

Formulation Considerations for Autologous T Cell Drug Products

by Christopher F. van der Walle, Sonya Godbert, Gabriele Saito and Zein Azhari

Pharmaceutics 2021, 13(8), 1317; https://doi.org/10.3390/pharmaceutics13081317 - 23 Aug 2021

Cited by 8 | Viewed by 8872

Abstract

Genetically modified autologous T cells have become an established immunotherapy in the fight against cancer. The manufacture of chimeric antigen receptor (CAR) and αβ-T cell receptor (TCR) transduced T cells poses unique challenges, including the formulation, cryopreservation and fill–finish steps, which are the [...] Read more.

Genetically modified autologous T cells have become an established immunotherapy in the fight against cancer. The manufacture of chimeric antigen receptor (CAR) and αβ-T cell receptor (TCR) transduced T cells poses unique challenges, including the formulation, cryopreservation and fill–finish steps, which are the focus of this review. With an increasing number of marketing approvals for CAR-T cell therapies, comparison of their formulation design and presentation for administration can be made. These differences will be discussed alongside the emergence of automated formulation and fill-finish processes, the formulation design space, Monte Carlo simulation applied to risk analysis, primary container selection, freezing profiles and thaw and the use of dimethyl sulfoxide and alternative solvents/excipients as cryopreservation agents. The review will conclude with a discussion of the pharmaceutical solutions required to meet the simplification of manufacture and flexibility in dosage form for clinical treatment. Full article

(This article belongs to the Section Gene and Cell Therapy)

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14 pages, 1744 KiB

Open AccessArticle

Metabolism of Diterpenoids Derived from the Bark of Cinnamomum cassia in Human Liver Microsomes

by Su Min Choi, Van Cong Pham, Sangkyu Lee and Jeong Ah Kim

Pharmaceutics 2021, 13(8), 1316; https://doi.org/10.3390/pharmaceutics13081316 - 23 Aug 2021

Cited by 5 | Viewed by 2886

Abstract

Cinnamomum cassia L. is used as a spice and flavoring agent as well as a traditional medicine worldwide. Diterpenoids, a class of compounds present in C. cassia, have various pharmacological effects, such as anti-inflammatory, antitumor, and antibacterial activities; however, there are [...] Read more.

Cinnamomum cassia L. is used as a spice and flavoring agent as well as a traditional medicine worldwide. Diterpenoids, a class of compounds present in C. cassia, have various pharmacological effects, such as anti-inflammatory, antitumor, and antibacterial activities; however, there are insufficient studies on the metabolism of diterpenoids. In this study, the metabolism of seven diterpenoids, namely, anhydrocinnzeylanol, anhydrocinnzeylanine (AHC), cinncassiol A, cinncassiol B, cinnzeylanol, cinnzeylanone, and cinnzeylanine, obtained from the bark of C. cassia was studied in human liver microsomes (HLMs). All studied diterpenoids, except for AHC, exhibited strong metabolic stability; however, AHC was rapidly metabolized to 3% in HLMs in the presence of β-NADPH. Using a high-resolution quadrupole-orbitrap mass spectrometer, 20 metabolites were identified as dehydrogenated metabolites (M1–M3), dehydrogenated and oxidated metabolites (M4–M10), mono-oxidated metabolites (M11–M13), or dioxidated metabolites (M14–M20). In addition, CYP isoforms involved in AHC metabolism were determined by profiling metabolites produced after incubation in 11 recombinant cDNA-expressed CYP isoforms. Thus, the diterpenoid compound AHC was identified in a metabolic pathway involving CYP3A4 in HLMs. Full article

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

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20 pages, 3563 KiB

Open AccessArticle

Improved Bioavailability of Ebastine through Development of Transfersomal Oral Films

by Nayyer Islam, Muhammad Irfan, Ameer Fawad Zahoor, Muhammad Shahid Iqbal, Haroon Khalid Syed, Ikram Ullah Khan, Akhtar Rasul, Salah-Ud-Din Khan, Alaa M. Alqahtani, Muzzamil Ikram, Muhammad Abdul Qayyum, Ahmed Khames, Sana Inam and Mohammed A. S. Abourehab

Pharmaceutics 2021, 13(8), 1315; https://doi.org/10.3390/pharmaceutics13081315 - 23 Aug 2021

Cited by 16 | Viewed by 3967

Abstract

The main objective of this research work was the development and evaluation of transfersomes integrated oral films for the bioavailability enhancement of Ebastine (EBT) to treat allergic rhinitis. The flexible transfersomes, consisting of drug (EBT), lipid (Phosphatidylcholine) and edge activator (EA) Polyoxyethylene sorbitan [...] Read more.

The main objective of this research work was the development and evaluation of transfersomes integrated oral films for the bioavailability enhancement of Ebastine (EBT) to treat allergic rhinitis. The flexible transfersomes, consisting of drug (EBT), lipid (Phosphatidylcholine) and edge activator (EA) Polyoxyethylene sorbitan monooleate or Sorbitan monolaurate, were prepared with the conventional thin film hydration method. The developed transfersomes were further integrated into oral films using the solvent casting method. Transfersomes were evaluated for their size distribution, surface charge, entrapment efficiency (EE%) and relative deformability, whereas the formulated oral films were characterized for weight, thickness, pH, folding endurance, tensile strength, % of elongation, degree of crystallinity, water content, content uniformity, in vitro drug release and ex vivo permeation, as well as in vivo pharmacokinetic and pharmacodynamics profile. The mean hydrodynamic diameter of transfersomes was detected to be 75.87 ± 0.55 nm with an average PDI and zeta potential of 0.089 ± 0.01 and 33.5 ± 0.39 mV, respectively. The highest deformability of transfersomes of 18.52 mg/s was observed in the VS-3 formulation. The average entrapment efficiency of the transfersomes was about 95.15 ± 1.4%. Transfersomal oral films were found smooth with an average weight, thickness and tensile strength of 174.72 ± 2.3 mg, 0.313 ± 0.03 mm and 36.4 ± 1.1 MPa, respectively. The folding endurance, pH and elongation were found 132 ± 1, 6.8 ± 0.2 and 10.03 ± 0.4%, respectively. The ex vivo permeability of EBT from formulation ETF-5 was found to be approximately 2.86 folds higher than the pure drug and 1.81 folds higher than plain film (i.e., without loaded transfersomes). The relative oral bioavailability of ETF-5 was 2.95- and 1.7-fold higher than that of EBT-suspension and plain film, respectively. In addition, ETF-5 suppressed the wheal and flare completely within 24 h. Based on the physicochemical considerations, as well as in vitro and in vivo characterizations, it is concluded that the highly flexible transfersomal oral films (TOFs) effectively improved the bioavailability and antihistamine activity of EBT. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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36 pages, 2871 KiB

Open AccessReview

Ectopic Odorant Receptor Responding to Flavor Compounds: Versatile Roles in Health and Disease

by Tao Tong, Yanan Wang, Seong-Gook Kang and Kunlun Huang

Pharmaceutics 2021, 13(8), 1314; https://doi.org/10.3390/pharmaceutics13081314 - 23 Aug 2021

Cited by 29 | Viewed by 6894

Abstract

Prompted by the ground-breaking discovery of the rodent odorant receptor (OR) gene family within the olfactory epithelium nearly 30 years ago, followed by that of OR genes in cells of the mammalian germ line, and potentiated by the identification of ORs throughout the [...] Read more.

Prompted by the ground-breaking discovery of the rodent odorant receptor (OR) gene family within the olfactory epithelium nearly 30 years ago, followed by that of OR genes in cells of the mammalian germ line, and potentiated by the identification of ORs throughout the body, our appreciation for ORs as general chemoreceptors responding to odorant compounds in the regulation of physiological or pathophysiological processes continues to expand. Ectopic ORs are now activated by a diversity of flavor compounds and are involved in diverse physiological phenomena varying from adipogenesis to myogenesis to hepatic lipid accumulation to serotonin secretion. In this review, we outline the key biological functions of the ectopic ORs responding to flavor compounds and the underlying molecular mechanisms. We also discuss research opportunities for utilizing ectopic ORs as therapeutic strategies in the treatment of human disease as well as challenges to be overcome in the future. The recognition of the potent function, signaling pathway, and pharmacology of ectopic ORs in diverse tissues and cell types, coupled with the fact that they belong to G protein-coupled receptors, a highly druggable protein family, unequivocally highlight the potential of ectopic ORs responding to flavor compounds, especially food-derived odorant compounds, as a promising therapeutic strategy for various diseases. Full article

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23 pages, 2632 KiB

Open AccessReview

Recent Progress in Drug Release Testing Methods of Biopolymeric Particulate System

by Yejin Kim, Eun Ji Park, Tae Wan Kim and Dong Hee Na

Pharmaceutics 2021, 13(8), 1313; https://doi.org/10.3390/pharmaceutics13081313 - 23 Aug 2021

Cited by 49 | Viewed by 7067

Abstract

Biopolymeric microparticles have been widely used for long-term release formulations of short half-life chemicals or synthetic peptides. Characterization of the drug release from microparticles is important to ensure product quality and desired pharmacological effect. However, there is no official method for long-term release [...] Read more.

Biopolymeric microparticles have been widely used for long-term release formulations of short half-life chemicals or synthetic peptides. Characterization of the drug release from microparticles is important to ensure product quality and desired pharmacological effect. However, there is no official method for long-term release parenteral dosage forms. Much work has been done to develop methods for in vitro drug release testing, generally grouped into three major categories: sample and separate, dialysis membrane, and continuous flow (flow-through cell) methods. In vitro drug release testing also plays an important role in providing insight into the in vivo performance of a product. In vitro release test with in vivo relevance can reduce the cost of conducting in vivo studies and accelerate drug product development. Therefore, investigation of the in vitro–in vivo correlation (IVIVC) is increasingly becoming an essential part of particulate formulation development. This review summarizes the principles of the in vitro release testing methods of biopolymeric particulate system with the recent research articles and discusses their characteristics including IVIVC, accelerated release testing methods, and stability of encapsulated drugs. Full article

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

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14 pages, 1696 KiB

Open AccessArticle

Nanostructured Lipid Carriers (NLCs) for Oral Peptide Drug Delivery: About the Impact of Surface Decoration

by Iram Shahzadi, Andrea Fürst, Patrick Knoll and Andreas Bernkop-Schnürch

Pharmaceutics 2021, 13(8), 1312; https://doi.org/10.3390/pharmaceutics13081312 - 22 Aug 2021

Cited by 19 | Viewed by 4045

Abstract

This study was aimed to evaluate the impact of surfactants used for nanostructured lipid carriers (NLCs) to provide enzymatic protection for incorporated peptides. Insulin as a model peptide was ion paired with sodium dodecyl sulfate to improve its lipophilicity. Three NLC formulations containing [...] Read more.

This study was aimed to evaluate the impact of surfactants used for nanostructured lipid carriers (NLCs) to provide enzymatic protection for incorporated peptides. Insulin as a model peptide was ion paired with sodium dodecyl sulfate to improve its lipophilicity. Three NLC formulations containing polyethylene glycol ester (PEG-ester), polyethylene glycol ether (PEG-ether), and polyglycerol ester (PG-ester) surfactants were prepared by solvent diffusion method. NLCs were characterized regarding particle size, polydispersity index, and zeta potential. Biocompatibility of NLCs was assessed on Caco-2 cells via resazurin assay. In vitro lipolysis study was performed using a standard lipid digestion method. Proteolytic studies were performed in simulated gastric fluid containing pepsin and simulated intestinal fluid containing pancreatin. Lipophilicity of insulin in terms of log P_{octanol/water} was improved from −1.8 to 2.1. NLCs were in the size range of 64–217 nm with a polydispersity index of 0.2–0.5 and exhibited a negative surface charge. PG-ester NLCs were non-cytotoxic up to a concentration of 0.5%, PEG-ester NLCs up to a concentration of 0.25% and PEG-ether NLC up to a concentration of 0.125% (w/v). The lipolysis study showed the release of >90%, 70%, and 10% of free fatty acids from PEG-ester, PG-ester, and PEG-ether NLCs, respectively. Proteolysis results revealed the highest protective effect of PEG-ether NLCs followed by PG-ester and PEG-ester NLCs for incorporated insulin complex. Findings suggest that NLCs bearing substructures less susceptible to degrading enzymes on their surface can provide higher protection for incorporated peptides toward gastrointestinal proteases. Full article

(This article belongs to the Special Issue Non-invasive Delivery of Biologics: Formulation Strategies and Regulatory Aspects)

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32 pages, 1001 KiB

Open AccessReview

Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms

by John Wahlich

Pharmaceutics 2021, 13(8), 1311; https://doi.org/10.3390/pharmaceutics13081311 - 22 Aug 2021

Cited by 25 | Viewed by 10371

Abstract

Continuous manufacturing (CM) is defined as a process in which the input material(s) are continuously fed into and transformed, and the processed output materials are continuously removed from the system. CM can be considered as matching the FDA’s so-called ‘Desired State’ of pharmaceutical [...] Read more.

Continuous manufacturing (CM) is defined as a process in which the input material(s) are continuously fed into and transformed, and the processed output materials are continuously removed from the system. CM can be considered as matching the FDA’s so-called ‘Desired State’ of pharmaceutical manufacturing in the twenty-first century as discussed in their 2004 publication on ‘Innovation and Continuous Improvement in Pharmaceutical Manufacturing’. Yet, focused attention on CM did not really start until 2014, and the first product manufactured by CM was only approved in 2015. This review describes some of the benefits and challenges of introducing a CM process with a particular focus on small molecule solid oral dosage forms. The review is a useful introduction for individuals wishing to learn more about CM. Full article

(This article belongs to the Special Issue Continuous Pharmaceutical Manufacturing, Volume II)

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22 pages, 7848 KiB

Open AccessArticle

Mild Hyperthermia Responsive Liposomes for Enhanced In Vitro and In Vivo Anticancer Efficacy of Doxorubicin against Hepatocellular Carcinoma

by Muhammad Abdur Rahim, Asadullah Madni, Nayab Tahir, Nasrullah Jan, Hassan Shah, Safiullah Khan, Riaz Ullah, Ahmed Bari and Muhammad Sohaib Khan

Pharmaceutics 2021, 13(8), 1310; https://doi.org/10.3390/pharmaceutics13081310 - 21 Aug 2021

Cited by 18 | Viewed by 2727

Abstract

The current study is aimed to fabricate doxorubicin (Dox) loaded mild temperature responsive liposomes (MTLs) by thin film hydration technique for enhanced in vitro and in vivo anticancer efficacy against hepatocellular carcinoma. The aforementioned Dox loaded MTLs were developed and optimized with extrusion [...] Read more.

The current study is aimed to fabricate doxorubicin (Dox) loaded mild temperature responsive liposomes (MTLs) by thin film hydration technique for enhanced in vitro and in vivo anticancer efficacy against hepatocellular carcinoma. The aforementioned Dox loaded MTLs were developed and optimized with extrusion and drug loading techniques. The optimized MTLs were in optimum size range (118.20 ± 2.81–187.13 ± 4.15 nm), colloidal stability (−13.27 ± 0.04 to −32.34 ± 0.15 mV), and enhanced entrapment of Dox (28.71 ± 2.01–79.24 ± 2.16). Furthermore, the optimized formulation (MTL1-E_(AL)) embodied improved physicochemical stability deducted by Fourier transform infra-red (FTIR) spectroscopy and mild hyperthermia-based phase transition demonstrated from differential scanning calorimetry (DSC). An in vitro drug release study revealed mild hyperthermia assisted rapid in vitro Dox release from MTLs-E_(AL) (T_100% ≈ 1 h) by Korsmeyer–Peppas model based Fickian diffusion (n < 0.45). Likewise, an in vitro cytotoxicity study and lower IC₅₀ values also symbolized mild hyperthermia (40.2 °C) based quick and improved cytotoxicity of MTL1-E_(AL) in HepG2 and MCF-7 cells than Dox. The fluorescence microscopy also represented enhanced cellular internalization of MTL1-E_(AL) at mild hyperthermia compared to the normothermia (37.2 °C). In addition, an in vivo animal study portrayed the safety, improved anticancer efficacy and healing of hepatocellular carcinoma (HCC) through MTL1-E_(AL). In brief, the Dox loaded MTLs could be utilized as safe and effective therapeutic strategy against HCC. Full article

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12 pages, 1285 KiB

Open AccessArticle

Efficacy of Combined Rifampicin Formulations Delivered by the Pulmonary Route to Treat Tuberculosis in the Guinea Pig Model

by Lucila Garcia-Contreras, Vasu Sethuraman, Masha Kazantseva and Anthony Hickey

Pharmaceutics 2021, 13(8), 1309; https://doi.org/10.3390/pharmaceutics13081309 - 21 Aug 2021

Cited by 5 | Viewed by 2706

Abstract

Liposomes, as vehicles alone or in combination with rifampicin (RIF) microparticles (RMs), were evaluated as vehicles to enhance the permeation of RIF into granulomas. RIF liposomes (RLs) were extruded through a 0.1 µm polypropylene membrane. RMs were prepared by the solvent evaporation method. [...] Read more.

Liposomes, as vehicles alone or in combination with rifampicin (RIF) microparticles (RMs), were evaluated as vehicles to enhance the permeation of RIF into granulomas. RIF liposomes (RLs) were extruded through a 0.1 µm polypropylene membrane. RMs were prepared by the solvent evaporation method. Four weeks after infection, guinea pigs (GPs) were assigned to groups treated with a combination of RM-RLs or RLs alone. RLs were nebulized after extrusion whereas RMs were suspended in saline and nebulized to GPs in a nose-only inhalation chamber. Necropsy was performed after the treatment; the lungs and spleen were resected for bacteriology. RLs had mean diameters of 137.1 ± 33.7 nm whereas RMs had a projected area diameter of 2.48 µm. The volume diameter of RMs was 64 ± 1 µm, indicating that RMs were aggregated. The treatment of TB-infected GPs with RLs significantly reduced their lung bacterial burden and wet spleen weight compared with those treated with blank liposomes. The treatment of TB-infected animals with RM-RLs also reduced their lung bacterial burden and wet spleen weight even though these reductions were not statistically different. Based on these results, the permeation of RIF into granulomas appears to be enhanced when encapsulated into liposomes delivered by the pulmonary route. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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10 pages, 2305 KiB

Open AccessArticle

Processing Impact on In Vitro and In Vivo Performance of Solid Dispersions—A Comparison between Hot-Melt Extrusion and Spray Drying

by Yongjun Li, Amanda K. P. Mann, Dan Zhang and Zhen Yang

Pharmaceutics 2021, 13(8), 1307; https://doi.org/10.3390/pharmaceutics13081307 - 21 Aug 2021

Cited by 14 | Viewed by 4185

Abstract

Presently, a large number of drug molecules in development are BCS class II or IV compounds with poor aqueous solubility. Various novel solubilization techniques have been used to enhance drug solubility. Among them, amorphous solid dispersions (ASD), which convert a crystalline drug into [...] Read more.

Presently, a large number of drug molecules in development are BCS class II or IV compounds with poor aqueous solubility. Various novel solubilization techniques have been used to enhance drug solubility. Among them, amorphous solid dispersions (ASD), which convert a crystalline drug into an amorphous mixture of drug and polymer, have been demonstrated to be an effective tool in enhancing drug solubility and bioavailability. There are multiple ways to produce amorphous solid dispersions. The goal of the present study is to investigate two commonly used processing methods, hot-melt extrusion (HME) and spray drying, and their impact on drug bioperformance. The amorphous solid dispersions of a model compound, posaconazole (25% drug loading) in HPMCAS-MF, were successfully manufactured via the two processing routes, and the physicochemical properties, in vitro and in vivo performance of the resulting ASDs were characterized and compared. It was found that in vitro drug release of the ASDs from two-stage dissolution was significantly different. However, the two ASDs showed similar in vivo performance based on cynomolgus monkey PK studies. A mechanistic understanding of the in vitro and in vivo behaviors of the solid dispersions was discussed. Full article

(This article belongs to the Special Issue Amorphous Solid Dispersions of Poorly Soluble Drugs: Materials Science and Engineering Perspective)

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14 pages, 3831 KiB

Open AccessArticle

A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice

by Songyi Seo, Koung Li Kim, Yeongju Yeo, Ryul-I Kim, Hayoung Jeong, Jin-Ock Kim, Sun-Hwa Song, Mi-Jin An, Jung-Woong Kim, Hye Kyoung Hong, Min Hee Ham, Se Joon Woo, Jong-Hyuk Sung, Sang Gyu Park and Wonhee Suh

Pharmaceutics 2021, 13(8), 1308; https://doi.org/10.3390/pharmaceutics13081308 - 20 Aug 2021

Cited by 2 | Viewed by 3050

Abstract

Stem cell factor (SCF) and its receptor, cKIT, are novel regulators of pathological neovascularization in the eye, which suggests that inhibition of SCF/cKIT signaling may be a novel pharmacological strategy for treating neovascular age-related macular degeneration (AMD). This study evaluated the therapeutic potential [...] Read more.

Stem cell factor (SCF) and its receptor, cKIT, are novel regulators of pathological neovascularization in the eye, which suggests that inhibition of SCF/cKIT signaling may be a novel pharmacological strategy for treating neovascular age-related macular degeneration (AMD). This study evaluated the therapeutic potential of a newly developed fully human monoclonal antibody targeting cKIT, NN2101, in a murine model of neovascular AMD. In hypoxic human endothelial cells, NN2101 substantially inhibited the SCF-induced increase in angiogenesis and activation of the cKIT signaling pathway. In a murine model of neovascular AMD, intravitreal injection of NN2101 substantially inhibited the SCF/cKIT-mediated choroidal neovascularization (CNV), with efficacy comparable to aflibercept, a vascular endothelial growth factor inhibitor. A combined intravitreal injection of NN2101 and aflibercept resulted in an additive therapeutic effect on CNV. NN2101 neither caused ocular toxicity nor interfered with the early retinal vascular development in mice. Ocular pharmacokinetic analysis in rabbits indicated that NN2101 demonstrated a pharmacokinetic profile suitable for intravitreal injection. These findings provide the first evidence of the potential use of the anti-cKIT blocking antibody, NN2101, as an alternative or additive therapeutic for the treatment of neovascular AMD. Full article

(This article belongs to the Section Biologics and Biosimilars)

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17 pages, 9896 KiB

Open AccessArticle

Effect of Selected Antidepressants on Placental Homeostasis of Serotonin: Maternal and Fetal Perspectives

by Hana Horackova, Rona Karahoda, Lukas Cerveny, Veronika Vachalova, Ronja Ebner, Cilia Abad and Frantisek Staud

Pharmaceutics 2021, 13(8), 1306; https://doi.org/10.3390/pharmaceutics13081306 - 20 Aug 2021

Cited by 22 | Viewed by 4824

Abstract

Depression is a prevalent condition affecting up to 20% of pregnant women. Hence, more than 10% are prescribed antidepressant drugs, mainly serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs). We hypothesize that antidepressants disturb serotonin homeostasis in the fetoplacental [...] Read more.

Depression is a prevalent condition affecting up to 20% of pregnant women. Hence, more than 10% are prescribed antidepressant drugs, mainly serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs). We hypothesize that antidepressants disturb serotonin homeostasis in the fetoplacental unit by inhibiting serotonin transporter (SERT) and organic cation transporter 3 (OCT3) in the maternal- and fetal-facing placental membranes, respectively. Paroxetine, citalopram, fluoxetine, fluvoxamine, sertraline, and venlafaxine were tested in situ (rat term placenta perfusion) and ex vivo (uptake studies in membrane vesicles isolated from healthy human term placenta). All tested antidepressants significantly inhibited SERT- and OCT3-mediated serotonin uptake in a dose-dependent manner. Calculated half-maximal inhibitory concentrations (IC₅₀) were in the range of therapeutic plasma concentrations. Using in vitro and in situ models, we further showed that the placental efflux transporters did not compromise mother-to-fetus transport of antidepressants. Collectively, we suggest that antidepressants have the potential to affect serotonin levels in the placenta or fetus when administered at therapeutic doses. Interestingly, the effect of antidepressants on serotonin homeostasis in rat placenta was sex dependent. As accurate fetal programming requires optimal serotonin levels in the fetoplacental unit throughout gestation, inhibition of SERT-/OCT3-mediated serotonin uptake may help explain the poor outcomes of antidepressant use in pregnancy. Full article

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18 pages, 1741 KiB

Open AccessArticle

Optimization and Evaluation of the In Vitro Permeation Parameters of Topical Products with Non-Steroidal Anti-Inflammatory Drugs through Strat-M^® Membrane

by Bartłomiej Milanowski, Hanna Wosicka-Frąckowiak, Eliza Główka, Małgorzata Sosnowska, Stanisław Woźny, Filip Stachowiak, Angelika Suchenek and Dariusz Wilkowski

Pharmaceutics 2021, 13(8), 1305; https://doi.org/10.3390/pharmaceutics13081305 - 20 Aug 2021

Cited by 17 | Viewed by 4688

Abstract

Pharmaceutical products containing non-steroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed topical formulations used for analgesic and antirheumatic properties. These drugs must overcome the skin barrier to cause a therapeutic effect. Human skin has been widely used as a model to study [...] Read more.

Pharmaceutical products containing non-steroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed topical formulations used for analgesic and antirheumatic properties. These drugs must overcome the skin barrier to cause a therapeutic effect. Human skin has been widely used as a model to study in vitro drug diffusion and permeation, however, it suffers from many limitations. Therefore, to perform in vitro permeation test (IVPT), we used a Strat-M^® membrane with diffusion characteristics well-correlated to human skin. This study’s objective was to optimize the IVPT conditions using Plackett–Burman experimental design for bio-predictive evaluation of the in vitro permeation rates of five non-steroidal anti-inflammatory drugs (diclofenac, etofenamate, ibuprofen, ketoprofen, naproxen) across Strat-M^® membrane from commercial topical formulations. The Plackett–Burman factorial design was used to screen the effect of seven factors in eight runs with one additional center point. This tool allowed us to set the sensitive and discriminative IVPT final conditions that can appropriately characterize the NSAIDs formulations. The permeation rate of etofenamate (ETF) across the Strat-M^® membrane was 1.7–14.8 times faster than other NSAIDs from selected semisolids but 1.6 times slower than the ETF spray formulation. Full article

(This article belongs to the Special Issue Impact of Physicochemical Properties of Pharmaceutical Substances on Dosage Form Performance)

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14 pages, 3131 KiB

Open AccessArticle

Probucol Pharmacological and Bio-Nanotechnological Effects on Surgically Transplanted Graft Due to Powerful Anti-Inflammatory, Anti-Fibrotic and Potential Bile Acid Modulatory Actions

by Armin Mooranian, Corina Mihaela Ionescu, Susbin Raj Wagle, Bozica Kovacevic, Daniel Walker, Melissa Jones, Jacqueline Chester, Thomas Foster, Edan Johnston, Momir Mikov, Marcus D. Atlas and Hani Al-Salami

Pharmaceutics 2021, 13(8), 1304; https://doi.org/10.3390/pharmaceutics13081304 - 20 Aug 2021

Cited by 9 | Viewed by 2549

Abstract

Introduction. A major obstacle in islet transplantation and graft survival pre and post transplantation is islet apoptosis due to mainly inflammatory bio molecules released during islet harvesting and post graft transplantation and hence, subsequent graft fibrosis and failure. This study aimed to investigate [...] Read more.

Introduction. A major obstacle in islet transplantation and graft survival pre and post transplantation is islet apoptosis due to mainly inflammatory bio molecules released during islet harvesting and post graft transplantation and hence, subsequent graft fibrosis and failure. This study aimed to investigate if incorporation of the anti-inflammatory anti-hyperlipidaemic drug probucol (PB) would improve islet-graft survival and function, post transplantation in Type 1 diabetes (T1D). Methods. T1D was induced in mice, and biological profiles of the diabetic mice transplanted PB-microencapsulated islets harvested from healthy syngeneic mice were measured. Results and Conclusion. Compared with sham (no PB), the treated group showed significant reduction in serum levels of interleukin-1β, interleukin-6, interleukin-12, interleukin-17, and tumour necrosis factor-α, accompanied by a 3-fold increase in survival duration, which suggests PB islet-protective effects, post transplantation. Full article

(This article belongs to the Special Issue Advances in Micro/Nanotechnology in Drug Delivery)

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15 pages, 2799 KiB

Open AccessArticle

Terahertz and Raman Spectroscopic Investigation of Monohydrate Cocrystal of Antitubercular Isoniazid with Protocatechuic Acid

by Yanhua Bo, Jiyuan Fang, Ziming Zhang, Jiadan Xue, Jianjun Liu, Zhi Hong and Yong Du

Pharmaceutics 2021, 13(8), 1303; https://doi.org/10.3390/pharmaceutics13081303 - 20 Aug 2021

Cited by 21 | Viewed by 2677

Abstract

Pharmaceutical cocrystal provides an alternative modification strategy for the formulation development of drugs owning to their potential ability to improve the physicochemical properties of active pharmaceutical ingredients (APIs) efficiently by changing inter-molecular interactions between raw materials. Isoniazid (INH) is an indispensable main drug [...] Read more.

Pharmaceutical cocrystal provides an alternative modification strategy for the formulation development of drugs owning to their potential ability to improve the physicochemical properties of active pharmaceutical ingredients (APIs) efficiently by changing inter-molecular interactions between raw materials. Isoniazid (INH) is an indispensable main drug for the treatment of tuberculosis, but its tablet formulation is unstable and prone to degradation. In the present study, the monohydrate cocrystal of INH and protocatechuic acid (PA) was prepared by solvent evaporation using PA as cocrystal former to optimize the properties of INH. The parent materials and corresponding 1:1 molar ratio INH-PA monohydrate cocrystal have been characterized by the terahertz time-domain (THz-TDS) and Raman spectroscopy. The THz absorption spectra displayed that there were obvious differences between the peaks of experimental cocrystal and the parent materials, and the same situation was found in Raman vibrational spectra. In addition, density functional theory (DFT) was applied to simulating and optimizing the structure of INH-PA monohydrate cocrystal and supplied corresponding vibrational modes. Our results provided a unique method to characterize the formation of INH-PA monohydrate cocrystal at the molecular-level and a lot of information about cocrystal structure and intra-molecular and/or inter-molecular hydrogen bond interactions in the emerging pharmaceutical cocrystal fields. Full article

(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery (Volume II))

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32 pages, 1770 KiB

Open AccessReview

Modelling Tools to Characterize Acetaminophen Pharmacokinetics in the Pregnant Population

by Sofie A. M. Brookhuis, Karel Allegaert, Lidwien M. Hanff, Marjolijn N. Lub-de Hooge, André Dallmann and Paola Mian

Pharmaceutics 2021, 13(8), 1302; https://doi.org/10.3390/pharmaceutics13081302 - 20 Aug 2021

Cited by 9 | Viewed by 3924

Abstract

This review describes acetaminophen pharmacokinetics (PK) throughout pregnancy, as analyzed by three methods (non-compartmental analyses (NCA), population PK, and physiologically based PK (PBPK) modelling). Eighteen studies using NCA were reported in the scientific literature. These studies reported an increase in the volume of [...] Read more.

This review describes acetaminophen pharmacokinetics (PK) throughout pregnancy, as analyzed by three methods (non-compartmental analyses (NCA), population PK, and physiologically based PK (PBPK) modelling). Eighteen studies using NCA were reported in the scientific literature. These studies reported an increase in the volume of distribution (3.5–60.7%) and an increase in the clearance (36.8–84.4%) of acetaminophen in pregnant women compared to non-pregnant women. Only two studies using population PK modelling as a technique were available in the literature. The largest difference in acetaminophen clearance (203%) was observed in women at delivery compared to non-pregnant women. One study using the PBPK technique was found in the literature. This study focused on the formation of metabolites, and the toxic metabolite N-acetyl-p-benzoquinone imine was the highest in the first trimester, followed by the second and third trimester, compared with non-pregnant women. In conclusion, this review gave an overview on acetaminophen PK changes in pregnancy. Also, knowledge gaps, such as fetal and placenta PK parameters, have been identified, which should be explored further before dosing adjustments can be suggested on an evidence-based basis. Full article

(This article belongs to the Special Issue Drugs in Pregnancy and Lactation)

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14 pages, 4478 KiB

Open AccessArticle

Personalised Tasted Masked Chewable 3D Printed Fruit-Chews for Paediatric Patients

by Atabak Ghanizadeh Tabriz, Daniel Henri George Fullbrook, Lilian Vilain, Youri Derrar, Uttom Nandi, Clara Grau, Anaïs Morales, Gemma Hooper, Zoltan Hiezl and Dennis Douroumis

Pharmaceutics 2021, 13(8), 1301; https://doi.org/10.3390/pharmaceutics13081301 - 20 Aug 2021

Cited by 30 | Viewed by 4607

Abstract

The development of personalised paediatric dosage forms using 3D printing technologies has gained significant interest over the last few years. In the current study extruded filaments of the highly bitter Diphenhydramine Hydrochloride (DPH) were fabricated by using suitable hydrophilic carries such as hydroxypropyl [...] Read more.

The development of personalised paediatric dosage forms using 3D printing technologies has gained significant interest over the last few years. In the current study extruded filaments of the highly bitter Diphenhydramine Hydrochloride (DPH) were fabricated by using suitable hydrophilic carries such as hydroxypropyl cellulose (Klucel ELF^TM) and a non-ionic surfactant (Gelucire 48/16^TM) combined with sweetener (Sucralose) and strawberry flavour grades. The thermoplastic filaments were used to print 3D fruit-chew designs by Fused Deposition Modelling (FDM) technology. Physicochemical characterisation confirmed the formation of glass solution where DPH was molecularly dispersed within the hydrophilic carriers. DPH was released rapidly from the 3D printed fruit-chew designs with >85% within the first 30 min. Trained panellists performed a full taste and sensory evaluation of the sweetener intensity and the strawberry aroma. The evaluation showed complete taste masking of the bitter DPH and revealed a synergistic effect of the sweetener and the strawberry flavour with enhanced sweet strawberry, fruity and aftertaste perception. The findings of the study can be used for the development of paediatric dosage forms with enhanced organoleptic properties, palatability and medication adherence. Full article

(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)

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14 pages, 1663 KiB

Open AccessArticle

Pulmonary Delivery of Curcumin and Beclomethasone Dipropionate in a Multicomponent Nanosuspension for the Treatment of Bronchial Asthma

by Luca Casula, Francesco Lai, Elena Pini, Donatella Valenti, Chiara Sinico, Maria Cristina Cardia, Salvatore Marceddu, Giorgia Ailuno and Anna Maria Fadda

Pharmaceutics 2021, 13(8), 1300; https://doi.org/10.3390/pharmaceutics13081300 - 20 Aug 2021

Cited by 23 | Viewed by 3396

Abstract

Curcumin has shown a potential extraordinary activity as an add-on ingredient in asthma treatment, due to its immunomodulatory and anti-inflammatory mechanism of action. However, its low water solubility and bioavailability lead to a poor therapeutic effect, which can be overcome by its formulation [...] Read more.

Curcumin has shown a potential extraordinary activity as an add-on ingredient in asthma treatment, due to its immunomodulatory and anti-inflammatory mechanism of action. However, its low water solubility and bioavailability lead to a poor therapeutic effect, which can be overcome by its formulation as nanocrystals. The aim of this study was to prepare a multicomponent formulation for the delivery of curcumin (CUR) and beclomethasone dipropionate (BDP) into the lungs as water-based nanosuspensions (NS). Single component formulations (CUR-NS, BDP-NS) and a multicomponent formulation (CUR+BDP-NS) were prepared through a wet ball media milling technique, using P188 as a non-toxic stabilizer. Characterization was carried out in terms of size, size distribution, zeta potential, nanocrystals morphology, and solid-state properties. Moreover, the inhalation delivery efficiency was studied with Next Generation Impactor (NGI, Apparatus E Ph. Eu). CUR-NS was optimized and showed a long-term stability and improved nanocrystals apparent solubility. The three formulations exhibited a nanocrystal mean diameter in the range of 200–240 nm and a homogenous particle size distribution. Aggregation or sedimentation phenomena were not observed in the multicomponent formulation on 90 days storage at room temperature. Finally, the nebulization tests of the three samples showed optimal aerodynamic parameters and MMAD < 5 µm. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy)

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19 pages, 3952 KiB

Open AccessArticle

Model-Informed Repurposing of Medicines for SARS-CoV-2: Extrapolation of Antiviral Activity and Dose Rationale for Paediatric Patients

by Federico Romano, Salvatore D’Agate and Oscar Della Pasqua

Pharmaceutics 2021, 13(8), 1299; https://doi.org/10.3390/pharmaceutics13081299 - 19 Aug 2021

Cited by 6 | Viewed by 2808

Abstract

Repurposing of remdesivir and other drugs with potential antiviral activity has been the basis of numerous clinical trials aimed at SARS-CoV-2 infection in adults. However, expeditiously designed trials without careful consideration of dose rationale have often resulted in treatment failure and toxicity in [...] Read more.

Repurposing of remdesivir and other drugs with potential antiviral activity has been the basis of numerous clinical trials aimed at SARS-CoV-2 infection in adults. However, expeditiously designed trials without careful consideration of dose rationale have often resulted in treatment failure and toxicity in the target patient population, which includes not only adults but also children. Here we show how paediatric regimens can be identified using pharmacokinetic-pharmacodynamic (PKPD) principles to establish the target exposure and evaluate the implications of dose selection for early and late intervention. Using in vitro data describing the antiviral activity and published pharmacokinetic data for the agents of interest, we apply a model-based approach to assess the exposure range required for adequate viral clearance and eradication. Pharmacokinetic parameter estimates were subsequently used with clinical trial simulations to characterise the probability target attainment (PTA) associated with enhanced antiviral activity in the lungs. Our analysis shows that neither remdesivir, nor anti-malarial drugs can achieve the desirable target exposure range based on a mg/kg dosing regimen, due to a limited safety margin and high concentrations needed to ensure the required PTA. To date, there has been limited focus on suitable interventions for children affected by COVID-19. Most clinical trials have defined doses selection criteria empirically, without thorough evaluation of the PTA. The current results illustrate how model-based approaches can be used for the integration of clinical and nonclinical data, providing a robust framework for assessing the probability of pharmacological success and consequently the dose rationale for antiviral drugs for the treatment of SARS-CoV-2 infection in children. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process)

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11 pages, 2868 KiB

Open AccessArticle

Thermostable and Long-Circulating Albumin-Conjugated Arthrobacter globiformis Urate Oxidase

by Byungseop Yang and Inchan Kwon

Pharmaceutics 2021, 13(8), 1298; https://doi.org/10.3390/pharmaceutics13081298 - 19 Aug 2021

Cited by 8 | Viewed by 2858

Abstract

Urate oxidase derived from Aspergillus flavus has been investigated as a treatment for tumor lysis syndrome, hyperuricemia, and gout. However, its long-term use is limited owing to potential immunogenicity, low thermostability, and short circulation time in vivo. Recently, urate oxidase isolated from Arthrobacter [...] Read more.

Urate oxidase derived from Aspergillus flavus has been investigated as a treatment for tumor lysis syndrome, hyperuricemia, and gout. However, its long-term use is limited owing to potential immunogenicity, low thermostability, and short circulation time in vivo. Recently, urate oxidase isolated from Arthrobacter globiformis (AgUox) has been reported to be thermostable and less immunogenic than the Aspergillus-derived urate oxidase. Conjugation of human serum albumin (HSA) to therapeutic proteins has become a promising strategy to prolong circulation time in vivo. To develop a thermostable and long-circulating urate oxidase, we investigated the site-specific conjugation of HSA to AgUox based on site-specific incorporation of a clickable non-natural amino acid (frTet) and an inverse electron demand Diels–Alder reaction. We selected 14 sites for frTet incorporation using the ROSETTA design, a computational stability prediction program, among which AgUox containing frTet at position 196 (Ag12) exhibited enzymatic activity and thermostability comparable to those of wild-type AgUox. Furthermore, Ag12 exhibited a high HSA conjugation yield without compromising the enzymatic activity, generating well-defined HSA-conjugated AgUox (Ag12-HSA). In mice, the serum half-life of Ag12-HSA was approximately 29 h, which was roughly 17-fold longer than that of wild-type AgUox. Altogether, this novel formulated AgUox may hold enhanced therapeutic efficacy for several diseases. Full article

(This article belongs to the Special Issue Albumin-Based Drug Delivery Systems)

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23 pages, 17846 KiB

Open AccessArticle

When Cyclodextrins Met Data Science: Unveiling Their Pharmaceutical Applications through Network Science and Text-Mining

by Juliana Rincón-López, Yara C. Almanza-Arjona, Alejandro P. Riascos and Yareli Rojas-Aguirre

Pharmaceutics 2021, 13(8), 1297; https://doi.org/10.3390/pharmaceutics13081297 - 19 Aug 2021

Cited by 14 | Viewed by 3769

Abstract

We present a data-driven approach to unveil the pharmaceutical technologies of cyclodextrins (CDs) by analyzing a dataset of CD pharmaceutical patents. First, we implemented network science techniques to represent CD patents as a single structure and provide a framework for unsupervised detection of [...] Read more.

We present a data-driven approach to unveil the pharmaceutical technologies of cyclodextrins (CDs) by analyzing a dataset of CD pharmaceutical patents. First, we implemented network science techniques to represent CD patents as a single structure and provide a framework for unsupervised detection of keywords in the patent dataset. Guided by those keywords, we further mined the dataset to examine the patenting trends according to CD-based dosage forms. CD patents formed complex networks, evidencing the supremacy of CDs for solubility enhancement and how this has triggered cutting-edge applications based on or beyond the solubility improvement. The networks exposed the significance of CDs to formulate aqueous solutions, tablets, and powders. Additionally, they highlighted the role of CDs in formulations of anti-inflammatory drugs, cancer therapies, and antiviral strategies. Text-mining showed that the trends in CDs for aqueous solutions, tablets, and powders are going upward. Gels seem to be promising, while patches and fibers are emerging. Cyclodextrins’ potential in suspensions and emulsions is yet to be recognized and can become an opportunity area. This is the first unsupervised/supervised data-mining approach aimed at depicting a landscape of CDs to identify trending and emerging technologies and uncover opportunity areas in CD pharmaceutical research. Full article

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

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18 pages, 24751 KiB

Open AccessArticle

Micellar Antibiotics of Bacillus

by William T. Ferreira, Huynh A. Hong, Mateusz Hess, James R. G. Adams, Hannah Wood, Karolina Bakun, Sisareuth Tan, Loredana Baccigalupi, Enrico Ferrari, Alain Brisson, Ezio Ricca, María Teresa Rejas, Wilfried J. J. Meijer, Mikhail Soloviev and Simon M. Cutting

Pharmaceutics 2021, 13(8), 1296; https://doi.org/10.3390/pharmaceutics13081296 - 19 Aug 2021

Cited by 11 | Viewed by 4283

Abstract

Members of the Bacillus genus, particularly the “Bacillus subtilis group”, are known to produce amphipathic lipopeptides with biosurfactant activity. This includes the surfactins, fengycins and iturins that have been associated with antibacterial, antifungal, and anti-viral properties. We have screened a large collection [...] Read more.

Members of the Bacillus genus, particularly the “Bacillus subtilis group”, are known to produce amphipathic lipopeptides with biosurfactant activity. This includes the surfactins, fengycins and iturins that have been associated with antibacterial, antifungal, and anti-viral properties. We have screened a large collection of Bacillus, isolated from human, animal, estuarine water and soil samples and found that the most potent lipopeptide producers are members of the species Bacillus velezensis. B. velezensis lipopeptides exhibited anti-bacterial activity which was localised on the surface of both vegetative cells and spores. Interestingly, lipopeptide micelles (6–10 nm diameter) were detectable in strains exhibiting the highest levels of activity. Micelles were stable (heat and gastric stable) and shown to entrap other antimicrobials produced by the host bacterium (exampled here was the dipeptide antibiotic chlorotetaine). Commercially acquired lipopeptides did not exhibit similar levels of inhibitory activity and we suspect that micelle formation may relate to the particular isomeric forms produced by individual bacteria. Using naturally produced micelle formulations we demonstrated that they could entrap antimicrobial compounds (e.g., clindamycin, vancomycin and resveratrol). Micellar incorporation of antibiotics increased activity. Bacillus is a prolific producer of antimicrobials, and this phenomenon could be exploited naturally to augment antimicrobial activity. From an applied perspective, the ability to readily produce Bacillus micelles and formulate with drugs enables a possible strategy for enhanced drug delivery. Full article

(This article belongs to the Special Issue Surfactants and Biomembranes: Which Implications in the Drug Delivery Field?)

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31 pages, 6452 KiB

Open AccessReview

Ruthenium Complexes: An Alternative to Platinum Drugs in Colorectal Cancer Treatment

by Kazi Mustafa Mahmud, Mahruba Sultana Niloy, Md Salman Shakil and Md Asiful Islam

Pharmaceutics 2021, 13(8), 1295; https://doi.org/10.3390/pharmaceutics13081295 - 19 Aug 2021

Cited by 40 | Viewed by 5422

Abstract

Colorectal cancer (CRC) is one of the intimidating causes of death around the world. CRC originated from mutations of tumor suppressor genes, proto-oncogenes and DNA repair genes. Though platinum (Pt)-based anticancer drugs have been widely used in the treatment of cancer, their toxicity [...] Read more.

Colorectal cancer (CRC) is one of the intimidating causes of death around the world. CRC originated from mutations of tumor suppressor genes, proto-oncogenes and DNA repair genes. Though platinum (Pt)-based anticancer drugs have been widely used in the treatment of cancer, their toxicity and CRC cells’ resistance to Pt drugs has piqued interest in the search for alternative metal-based drugs. Ruthenium (Ru)-based compounds displayed promising anticancer activity due to their unique chemical properties. Ru-complexes are reported to exert their anticancer activities in CRC cells by regulating different cell signaling pathways that are either directly or indirectly associated with cell growth, division, proliferation, and migration. Additionally, some Ru-based drug candidates showed higher potency compared to commercially available Pt-based anticancer drugs in CRC cell line models. Meanwhile Ru nanoparticles coupled with photosensitizers or anticancer agents have also shown theranostic potential towards CRC. Ru-nanoformulations improve drug efficacy, targeted drug delivery, immune activation, and biocompatibility, and therefore may be capable of overcoming some of the existing chemotherapeutic limitations. Among the potential Ru-based compounds, only Ru (III)-based drug NKP-1339 has undergone phase-Ib clinical trials in CRC treatment. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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54 pages, 7151 KiB

Open AccessReview

Lipid Nanocarriers for Anti-HIV Therapeutics: A Focus on Physicochemical Properties and Biotechnological Advances

by Maria J. Faria, Carla M. Lopes, José das Neves and Marlene Lúcio

Pharmaceutics 2021, 13(8), 1294; https://doi.org/10.3390/pharmaceutics13081294 - 19 Aug 2021

Cited by 16 | Viewed by 4481

Abstract

Since HIV was first identified, and in a relatively short period of time, AIDS has become one of the most devastating infectious diseases of the 21st century. Classical antiretroviral therapies were a major step forward in disease treatment options, significantly improving the survival [...] Read more.

Since HIV was first identified, and in a relatively short period of time, AIDS has become one of the most devastating infectious diseases of the 21st century. Classical antiretroviral therapies were a major step forward in disease treatment options, significantly improving the survival rates of HIV-infected individuals. Even though these therapies have greatly improved HIV clinical outcomes, antiretrovirals (ARV) feature biopharmaceutic and pharmacokinetic problems such as poor aqueous solubility, short half-life, and poor penetration into HIV reservoir sites, which contribute to the suboptimal efficacy of these regimens. To overcome some of these issues, novel nanotechnology-based strategies for ARV delivery towards HIV viral reservoirs have been proposed. The current review is focused on the benefits of using lipid-based nanocarriers for tuning the physicochemical properties of ARV to overcome biological barriers upon administration. Furthermore, a correlation between these properties and the potential therapeutic outcomes has been established. Biotechnological advancements using lipid nanocarriers for RNA interference (RNAi) delivery for the treatment of HIV infections were also discussed. Full article

(This article belongs to the Special Issue Controlled Release of Nanostructured Drug Systems)

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16 pages, 2331 KiB

Open AccessArticle

Development of Chitosan/Cyclodextrin Nanospheres for Levofloxacin Ocular Delivery

by Federica De Gaetano, Andreana Marino, Alessia Marchetta, Corrado Bongiorno, Roberto Zagami, Maria C. Cristiano, Donatella Paolino, Venerando Pistarà and Cinzia A. Ventura

Pharmaceutics 2021, 13(8), 1293; https://doi.org/10.3390/pharmaceutics13081293 - 19 Aug 2021

Cited by 29 | Viewed by 3792

Abstract

Levofloxacin (LVF) is an antibacterial drug approved for the treatment of ocular infections. However, due to the low ocular bioavailability, high doses are needed, causing bacterial resistance. Polymeric nanospheres (NPs) loading antibiotic drugs represent the most promising approach to eradicate ocular infections and [...] Read more.

Levofloxacin (LVF) is an antibacterial drug approved for the treatment of ocular infections. However, due to the low ocular bioavailability, high doses are needed, causing bacterial resistance. Polymeric nanospheres (NPs) loading antibiotic drugs represent the most promising approach to eradicate ocular infections and to treat pathogen resistance. In this study, we have developed chitosan NPs based on sulfobutyl-ether-β-cyclodextrin (CH/SBE-β-CD NPs) for ocular delivery of LVF. CH/SBE-β-CD NPs loading LVF were characterized in terms of encapsulation parameters, morphology, and sizes, in comparison to NPs produced without the macrocycle. Nuclear magnetic resonance and UV–vis spectroscopy studies demonstrated that SBE-β-CD is able to complex LVF and to influence encapsulation parameters of NPs, producing high encapsulation efficiency and LVF loading. The NPs were homogenous in size, with a hydrodynamic radius between 80 and 170 nm and positive zeta potential (ζ) values. This surface property could promote the interaction of NPs with the negatively charged ocular tissue, increasing their residence time and, consequently, LVF efficacy. In vitro, antibacterial activity against Gram-positive and Gram-negative bacteria showed a double higher activity of CH/SBE-β-CD NPs loading LVF compared to the free drug, suggesting that chitosan NPs based on SBE-β-CD could be a useful system for the treatment of ocular infections. Full article

(This article belongs to the Collection Women in Pharmaceutics)

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