Research

Jump to: Other

11 pages, 1095 KiB

Open AccessArticle

Potential Use of the Maillard Reaction for Pharmaceutical Applications: Gastric and Intestinal Controlled Release Alginate-Albumin Beads

by Mouhamad Khoder, Henry K. Gbormoi, Sr., Ali Ryan, Ayman Karam and Raid G. Alany

Pharmaceutics 2019, 11(2), 83; https://doi.org/10.3390/pharmaceutics11020083 - 15 Feb 2019

Cited by 15 | Viewed by 4820

Abstract

In this study, bovine serum albumin (BSA) and alginate (ALG) conjugates were synthesized by the Maillard reaction in order to evaluate their potential to develop controlled release drug delivery systems. The progress of the Maillard reaction was evidenced using ultraviolet (UV) absorbance, determination [...] Read more.

In this study, bovine serum albumin (BSA) and alginate (ALG) conjugates were synthesized by the Maillard reaction in order to evaluate their potential to develop controlled release drug delivery systems. The progress of the Maillard reaction was evidenced using ultraviolet (UV) absorbance, determination of BSA remaining free amino groups, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). BSA-ALG conjugates possessed enhanced and tunable viscosity, foamability and foam stability. Foam generated from BSA-ALG conjugate solution was used to prepare floating gastroretentive calcium ALG beads. Unlike traditional ALG beads, BSA-ALG foam beads were able to float and sustain the ciprofloxacin (CIP) release in gastric medium. Interestingly, intestinal beads made of ALG, BSA-ALG physical mixture and BSA-ALG conjugate resulted in different release rates and orders of indomethacin (IND) in simulated intestinal fluids; while beads based on a physical mixture of BSA-ALG resulted in a first order sustained release profile, both systems based on ALG and BSA-ALG conjugate displayed zero order sustained release profiles with IND being released at a slower rate from the conjugate beads. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

19 pages, 3914 KiB

Open AccessArticle

Localized Therapy of Vaginal Infections and Inflammation: Liposomes-In-Hydrogel Delivery System for Polyphenols

by May Wenche Jøraholmen, Purusotam Basnet, Mia Jonine Tostrup, Sabrin Moueffaq and Nataša Škalko-Basnet

Pharmaceutics 2019, 11(2), 53; https://doi.org/10.3390/pharmaceutics11020053 - 27 Jan 2019

Cited by 50 | Viewed by 5222

Abstract

Natural polyphenols, such as resveratrol (RES) or epicatechin (EPI), are attractive for treatments of various diseases, including vaginal infections and inflammation, because of their strong anti-oxidative and anti-inflammatory properties. However, their low solubility and consequent poor bioavailability limit their therapeutic uses. To overcome [...] Read more.

Natural polyphenols, such as resveratrol (RES) or epicatechin (EPI), are attractive for treatments of various diseases, including vaginal infections and inflammation, because of their strong anti-oxidative and anti-inflammatory properties. However, their low solubility and consequent poor bioavailability limit their therapeutic uses. To overcome these limitations, a vaginal delivery system comprising either RES or EPI liposomes-in-hydrogel was developed. This system permits therapeutic action of both liposomal polyphenol (RES or EPI) and chitosan-based hydrogel. Liposomes of around 200 nm and entrapment efficiency of 81% and 77% for RES and EPI, respectively, were incorporated into chitosan hydrogel, respectively. Medium molecular weight chitosan (2.5%, w/w) was found to have optimal texture properties and mucoadhesiveness in ex vivo conditions. The in vitro release studies confirmed the sustained release of polyphenols from the system. Both liposomal polyphenols and polyphenols-in-liposomes-in-hydrogel exhibited only minor effects on cell toxicity. EPI showed superior radical scavenging activity at lower concentrations compared to antioxidants vitamin C and E. Anti-inflammatory activity expressed as the inhibitory activity of formulations on the NO production in the LPS-induced macrophages (RAW 264.7) confirmed the superiority of EPI liposomes-in-hydrogel. The plain liposomes-in-hydrogel also exhibited potent anti-inflammatory activity, suggesting that chitosan hydrogel acts in synergy regarding anti-inflammatory effect of formulation. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

16 pages, 2968 KiB

Open AccessArticle

Comparative Analysis of Protein Quantification Methods for the Rapid Determination of Protein Loading in Liposomal Formulations

by Maryam T. Hussain, Neil Forbes and Yvonne Perrie

Pharmaceutics 2019, 11(1), 39; https://doi.org/10.3390/pharmaceutics11010039 - 18 Jan 2019

Cited by 21 | Viewed by 7336

Abstract

Advances in manufacturing processes provide the ability for the high throughput production of liposomes containing a range of moieties, from small molecules to large biologicals (including proteins and nucleic acids for prophylactic and therapeutic applications). Whilst rapid quantification methods for small molecules are [...] Read more.

Advances in manufacturing processes provide the ability for the high throughput production of liposomes containing a range of moieties, from small molecules to large biologicals (including proteins and nucleic acids for prophylactic and therapeutic applications). Whilst rapid quantification methods for small molecules are generally well established, the ability to rapidly quantify liposomal entrapment of proteins is limited. Indeed, most standard protein quantification techniques (including the BCA assay and Reverse phase-high performance liquid chromatography (RP-HPLC)) measure protein encapsulation indirectly, by measuring the amount of non-incorporated drug, and subtracting from the initial amount of protein added. However, this can give inaccurate and misrepresentative results. To address this, we have developed a range of methods to directly quantify protein entrapment within liposomes. The encapsulation efficiency within neutral, anionic and cationic liposome formulations was determined by three techniques; BCA assay, RP-HPLC and HPLC coupled to an evaporative light scattering detector, (HPLC-ELSD). All three methods are reliable for the quantification of protein, with linear responses and correlation coefficients of 0.99, and LOQ for all three methods being less than 10 µg/mL. Here within, we provide three methods for the rapid and robust quantification of protein loading within liposomal (and other bilayer) vesicle systems. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

11 pages, 1655 KiB

Open AccessArticle

Process Optimization and Upscaling of Spray-Dried Drug-Amino acid Co-Amorphous Formulations

by Georgia Kasten, Íris Duarte, Maria Paisana, Korbinian Löbmann, Thomas Rades and Holger Grohganz

Pharmaceutics 2019, 11(1), 24; https://doi.org/10.3390/pharmaceutics11010024 - 09 Jan 2019

Cited by 15 | Viewed by 3778

Abstract

The feasibility of upscaling the formulation of co-amorphous indomethacin-lysine from lab-scale to pilot-scale spray drying was investigated. A 2² full factorial design of experiments (DoE) was employed at lab scale. The atomization gas flow rate (F_atom, from 0.5 to 1.4 [...] Read more.

The feasibility of upscaling the formulation of co-amorphous indomethacin-lysine from lab-scale to pilot-scale spray drying was investigated. A 2² full factorial design of experiments (DoE) was employed at lab scale. The atomization gas flow rate (F_atom, from 0.5 to 1.4 kg/h) and outlet temperature (T_out, from 55 to 75 °C) were chosen as the critical process parameters. The obtained amorphization, glass transition temperature, bulk density, yield, and particle size distribution were chosen as the critical quality attributes. In general, the model showed low F_atom and high T_out to be beneficial for the desired product characteristics (a co-amorphous formulation with a low bulk density, high yield, and small particle size). In addition, only a low F_atom and high T_out led to the desired complete co-amorphization, while a minor residual crystallinity was observed with the other combinations of F_atom and T_out. Finally, upscaling to a pilot scale spray dryer was carried out based on the DoE results; however, the drying gas flow rate and the feed flow rate were adjusted to account for the different drying chamber geometries. An increased likelihood to achieve complete amorphization, because of the extended drying chamber, and hence an increased residence time of the droplets in the drying gas, was found in the pilot scale, confirming the feasibility of upscaling spray drying as a production technique for co-amorphous systems. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

19 pages, 2288 KiB

Open AccessArticle

Nanotoxicologic Effects of PLGA Nanoparticles Formulated with a Cell-Penetrating Peptide: Searching for a Safe pDNA Delivery System for the Lungs

by Larissa Gomes dos Reis, Wing-Hin Lee, Maree Svolos, Lyn Margaret Moir, Rima Jaber, Norbert Windhab, Paul Michael Young and Daniela Traini

Pharmaceutics 2019, 11(1), 12; https://doi.org/10.3390/pharmaceutics11010012 - 03 Jan 2019

Cited by 24 | Viewed by 4348

Abstract

The use of cell-penetrating peptides (CPPs) in combination with nanoparticles (NPs) shows great potential for intracellular delivery of DNA. Currently, its application is limited due to the potential toxicity and unknown long-term side effects. In this study NPs prepared using a biodegradable polymer, [...] Read more.

The use of cell-penetrating peptides (CPPs) in combination with nanoparticles (NPs) shows great potential for intracellular delivery of DNA. Currently, its application is limited due to the potential toxicity and unknown long-term side effects. In this study NPs prepared using a biodegradable polymer, poly(lactic–co–glycolic acid (PLGA) in association with a CPP, was assessed on two lung epithelial cell lines (adenocarcinomic human alveolar basal epithelial cells (A549) and normal bronchial epithelial cells (Beas-2B cells)). Addition of CPP was essential for intracellular internalization. No effects were observed on the mitochondrial activity and membrane integrity. Cells exposed to the NPs–DNA–CPP showed low inflammatory response, low levels of apoptosis and no activation of caspase-3. Increase in necrotic cells (between 10%–15%) after 24 h of incubation and increase in autophagy, induced by NPs–DNA–CPP, are likely to be related to the lysosomal escape mechanism. Although oxidative stress is one of the main toxic mechanisms of NPs, NPs–DNA–CPP showed decreased reactive oxygen species (ROS) production on Beas-2B cells, with potential antioxidant effect of CPP and no effect on A549 cells. This NP system appears to be safe for intracellular delivery of plasmid DNA to the lung epithelial cells. Further investigations should be conducted in other lung-related systems to better understand its potential effects on the lungs. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

10 pages, 601 KiB

Open AccessArticle

Potentially Inappropriate Prescribing of Oral Solid Medications in Elderly Dysphagic Patients

by Matteo Sestili, Serena Logrippo, Marco Cespi, Giulia Bonacucina, Letizia Ferrara, Silvia Busco, Iolanda Grappasonni, Giovanni Filippo Palmieri, Roberta Ganzetti and Paolo Blasi

Pharmaceutics 2018, 10(4), 280; https://doi.org/10.3390/pharmaceutics10040280 - 16 Dec 2018

Cited by 13 | Viewed by 4181

Abstract

Pharmaceutical formulations suitable for dysphagic patients are not always commercially available, motivating caregivers to crush tablets or open capsules to facilitate swallowing. Since this action may modify the characteristics of the medicine, it should be considered potentially inappropriate. This paper is the first [...] Read more.

Pharmaceutical formulations suitable for dysphagic patients are not always commercially available, motivating caregivers to crush tablets or open capsules to facilitate swallowing. Since this action may modify the characteristics of the medicine, it should be considered potentially inappropriate. This paper is the first to focus on how hospitalization affected the rate of potentially inappropriate prescriptions (PIPs) and the incidence of dosage form-related PIPs in elderly patients with dysphagia. Data was collected by reviewing patient medical records in the Italian National Research Center on Aging of Ancona. The therapy at admission and discharge was analysed in terms of: inappropriate drug associations, inappropriate drugs for dysphagic patients, inappropriate dosage forms and inappropriate dosage form modifications. Forty-one dysphagic patients with an average age of 88.3 years were included in the study and 451 prescriptions were analysed. PIPs were widespread at admission, and hospitalization did not improve the situation in a statistically significant manner. The most common PIPs identified (>80%) were related to dosage form selection and modification. This study highlights a clear need for continuing medical education about prescription appropriateness and modification of solid dosage forms in patients with dysphagia. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Figure 1

14 pages, 3323 KiB

Open AccessArticle

Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration

by Mikhail D. Murashov, Jennifer Diaz-Espinosa, Vernon LaLone, Joel W. Y. Tan, Raluca Laza, Xueding Wang, Kathleen A. Stringer and Gus R. Rosania

Pharmaceutics 2018, 10(4), 238; https://doi.org/10.3390/pharmaceutics10040238 - 17 Nov 2018

Cited by 17 | Viewed by 4423

Abstract

Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ [...] Read more.

Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ is a weakly basic, red phenazine dye, the skin pigmentation side effect results from lipophilic partitioning of the circulating, free base (neutral) form of CFZ into the skin. Here, we developed a stable and biocompatible formulation of CFZ-HCl microcrystals that mimics the predominant form of the drug that bioaccumulates in macrophages, following long term oral CFZ administration. In mice, intravenous injection of these biomimetic CFZ-HCl microcrystals led to visible drug accumulation in macrophages of the reticuloendothelial system with minimal skin accumulation or pigmentation. In fact, no skin pigmentation was observed when the total amount of CFZ-HCl administered was equivalent to the total oral dose leading to maximal skin pigmentation. Thus, parenteral (injected or inhaled) biomimetic formulations of CFZ-HCl could be instrumental to avoid the pigmentation side effect of oral CFZ therapy. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

15 pages, 2719 KiB

Open AccessArticle

Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs

by Chiara Di Meo, Mayte Martínez-Martínez, Tommasina Coviello, Marival Bermejo, Virginia Merino, Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez and Pietro Matricardi

Pharmaceutics 2018, 10(4), 213; https://doi.org/10.3390/pharmaceutics10040213 - 03 Nov 2018

Cited by 5 | Viewed by 3046

Abstract

Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack [...] Read more.

Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

18 pages, 3187 KiB

Open AccessArticle

Permeability Behavior of Nanocrystalline Solid Dispersion of Dipyridamole Generated Using NanoCrySP Technology

by Ashish Girdhar, Poonam Singh Thakur, Sneha Sheokand and Arvind K. Bansal

Pharmaceutics 2018, 10(3), 160; https://doi.org/10.3390/pharmaceutics10030160 - 17 Sep 2018

Cited by 12 | Viewed by 4507

Abstract

Nanocrystals research has been an area of significant interest lately, providing oral bioavailability benefits to solubility- and/or dissolution rate-limited drugs. Drug nanocrystals are generated using top-down or bottom-up technologies. Combination technologies (Nanoedge, Nanopure XP and SmartCrystal) have been recently developed to generate nanocrystals [...] Read more.

Nanocrystals research has been an area of significant interest lately, providing oral bioavailability benefits to solubility- and/or dissolution rate-limited drugs. Drug nanocrystals are generated using top-down or bottom-up technologies. Combination technologies (Nanoedge, Nanopure XP and SmartCrystal) have been recently developed to generate nanocrystals of improved properties. Our lab has also contributed in this field by providing a ‘novel’ platform technology, NanoCrySP, for the generation of nanocrystals. NanoCrySP-generated nanocrystals have improved the oral bioavailability of various molecules. In this study, we aim to assess the permeability behavior of nanocrystals generated by NanoCrySP. Three samples of Dipyridamole (DPM) drug were used in this study: (1) DPM (micron-sized powder), (2) nanocrystals of DPM (NS), generated by media milling (as control) and, (3) nanocrystalline solid dispersion containing DPM (NSD) in the matrix of mannitol (MAN), generated using NanoCrySP technology. In vitro (Caco-2 cell lines) and ex vivo (everted gut sac) studies were conducted in this work. Cellular permeability (P_app) from apical-to-basolateral side in Caco-2 cell monolayer was found to be in the order NS > NSD > DPM, which was the same as their apparent solubility values. Higher P_app from a basolateral-to-apical side suggested a significant contribution of the P-gp efflux transport for DPM, while NS exhibited much higher inhibition of the efflux mechanism than NSD. Both NS and NSD showed higher permeation from the jejunum region in the ex vivo everted gut sac study. Interestingly, P_app of NSD was similar to NS in ex vivo everted gut sac model, however, NSD showed higher mucoadhesion than NS and DPM in this study. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

13 pages, 24796 KiB

Open AccessArticle

Tannic Acid-Lung Fluid Assemblies Promote Interaction and Delivery of Drugs to Lung Cancer Cells

by Elham Hatami, Prashanth K. B. Nagesh, Pallabita Chowdhury, Subhash C. Chauhan, Meena Jaggi, Amali E. Samarasinghe and Murali M. Yallapu

Pharmaceutics 2018, 10(3), 111; https://doi.org/10.3390/pharmaceutics10030111 - 01 Aug 2018

Cited by 16 | Viewed by 4561

Abstract

Lung cancer (LC) is one of the leading causes of death in both men and women in the United States. Tannic acid (TA), a water-soluble polyphenol, exhibits a wide range of biological activities. TA has received much attention as a promising compound in [...] Read more.

Lung cancer (LC) is one of the leading causes of death in both men and women in the United States. Tannic acid (TA), a water-soluble polyphenol, exhibits a wide range of biological activities. TA has received much attention as a promising compound in the biomaterial and drug delivery fields. Lung fluid (LF) is a major barrier for distribution of drugs to the lungs. Therefore, the purpose of this study was to examine TA interaction with LF for effective delivery of anti-cancer drug molecules via pulmonary delivery. The extent of adsorption of LF proteins by TA was revealed by fluorescence quenching in fluorescence spectroscopy. The presence of LF in TA-LF complexes was noticed by the presence of protein peaks at 1653 cm⁻¹. Both protein dot and SDS-PAGE analysis confirmed LF protein complexation at all TA concentrations employed. A stable particle TA-LF complex formation was observed through transmission electron microscopy (TEM) analysis. The complexation pattern measured by dynamic light scattering (DLS) indicated that it varies depending on the pH of the solutions. The degree of LF presence in TA-LF complexes signifies its interactive behavior in LC cell lines. Such superior interaction offered an enhanced anti-cancer activity of drugs encapsulated in TA-LF complex nanoformulations. Our results indicate that TA binds to LF and forms self-assemblies, which profoundly enhance interaction with LC cells. This study demonstrated that TA is a novel carrier for pharmaceutical drugs such as gemcitabine, carboplatin, and irinotecan. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Figure 1

Other

Jump to: Research

17 pages, 3229 KiB

Open AccessConcept Paper

Prospects and Challenges of Phospholipid-Based Prodrugs

by Milica Markovic, Shimon Ben-Shabat, Shahar Keinan, Aaron Aponick, Ellen M. Zimmermann and Arik Dahan

Pharmaceutics 2018, 10(4), 210; https://doi.org/10.3390/pharmaceutics10040210 - 01 Nov 2018

Cited by 22 | Viewed by 5132

Abstract

Nowadays, the prodrug approach is used already at the early stages of drug development. Lipidic prodrug approach is a growing field for improving a number of drug properties/delivery/therapy aspects, and can offer solutions for various unmet needs. This approach includes drug moiety bound [...] Read more.

Nowadays, the prodrug approach is used already at the early stages of drug development. Lipidic prodrug approach is a growing field for improving a number of drug properties/delivery/therapy aspects, and can offer solutions for various unmet needs. This approach includes drug moiety bound to the lipid carrier, which can be triglyceride, fatty acids, steroid, or phospholipid (PL). The focus of this article is PL-based prodrugs, which includes a PL carrier covalently bound to the active drug moiety. An overview of relevant physiological lipid processing pathways and absorption barriers is provided, followed by drug delivery/therapeutic application of PL-drug conjugates, as well as computational modeling techniques, and a modern bioinformatics tool that can aid in the optimization of PL conjugates. PL-based prodrugs have increased lipophilicity comparing to the parent drug, and can therefore significantly improve the pharmacokinetic profile and overall bioavailability of the parent drug, join the endogenous lipid processing pathways and therefore accomplish drug targeting, e.g., by lymphatic transport, drug release at specific target site(s), or passing the blood-brain barrier. Moreover, an exciting gateway for treating inflammatory diseases and cancer is presented, by utilizing the PL sn-2 position in the prodrug design, aiming for PLA₂-mediated activation. Overall, a PL-based prodrug approach shows great potential in improving different drug delivery/therapy aspects, and is expected to grow. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Feature Papers for 10th Anniversary of Pharmaceutics

Share This Special Issue

Special Issue Editors

Special Issue Information

Published Papers (11 papers)

Research

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI