Arginine-based cationic surfactants: Biodegradable auxiliary agents for the formation of hydrophobic ion pairs with hydrophilic macromolecular drugs

Shahzadi, Iram; Asim, Mulazim Hussain; Dizdarević, Aida; Wolf, Julian Dominik; Kurpiers, Markus; Matuszczak, Barbara; Bernkop‐Schnürch, Andreas

doi:10.1016/j.jcis.2019.05.057

Cited by 39 publications

(28 citation statements)

References 33 publications

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“…The molecular mass of Cys-NAC was determined using LC–MS according to our previously used method with minor modification [ 19 ]. Mass spectrometry detection was carried out using a Chromaster 5610 MS detector (Hitachi) controlled by a computer running the MSD system manager software (version 2.1).…”

Section: Methodsmentioning

confidence: 99%

Less Reactive Thiol Ligands: Key towards Highly Mucoadhesive Drug Delivery Systems

et al. 2020

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As less reactive s-protected thiomers can likely interpenetrate the mucus gel layer to a higher extent before getting immobilized via disulfide bond formation with mucins, it was the aim of this study to develop a novel type of s-protected thiomer based on the less reactive substructure cysteine-N-acetyl cysteine (Cys-NAC) in order to obtain improved mucoadhesive properties. For this purpose, two types of s-protected thiomers, polyacrylic acid-cysteine-mercaptonicotinic acid (PAA-Cys-MNA) and polyacrylic acid-cysteine-N-acetyl cysteine (PAA-Cys-NAC), were synthesized and characterized by Fourier-transform infrared spectroscopy (FT-IR) and the quantification of attached disulfide ligands. The viscosity of both products was measured in the presence of NAC and mucus. Both thiomers were also evaluated regarding swelling behavior, tensile studies and retention time on the porcine intestinal mucosa. The FT-IR spectra confirmed the successful attachment of Cys-MNA and Cys-NAC ligands to PAA. The number of attached sulfhydryl groups was in the range of 660–683 µmol/g. The viscosity of both s-protected thiomers increased due to the addition of increasing amounts of NAC. The viscosity of the mucus increased in the presence of 1% PAA-Cys-MNA and PAA-Cys-NAC 5.6- and 10.9-fold, respectively, in comparison to only 1% PAA. Both s-protected thiomers showed higher water uptake than unmodified PAA. The maximum detachment force (MDF) and the total work of adhesion (TWA) increased in the case of PAA-Cys-MNA up to 1.4- and 1.6-fold and up to 2.4- and 2.8-fold in the case of PAA-Cys-NAC. The retention of PAA, PAA-Cys-MNA, and PAA-Cys-NAC on porcine intestinal mucosa was 25%, 49%, and 76% within 3 h, respectively. The results of this study provide evidence that less reactive s-protected thiomers exhibit higher mucoadhesive properties than highly reactive s-protected thiomers.

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Section: Methodsmentioning

confidence: 99%

Less Reactive Thiol Ligands: Key towards Highly Mucoadhesive Drug Delivery Systems

et al. 2020

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“…40 Researchers have recently reported efforts to synthesize arginine-based cationic surfactants for HIP, which should be both biodegradable and non-cytotoxic. 41 Specic considerations by drug molecule class Small molecules. Many small molecule drugs have only one ionic group.…”

Section: Thermodynamicsmentioning

confidence: 99%

“…Losartan Arginine-nonyl ester 41 Desmopressin Oleic acid 77 SEDDS 45,77,86,170 Sodium docusate 45,77,86,170 Sodium dodecyl sulfate 77,86 Sodium stearate 77 (note: less effective than SDS, AOT, and oleate) Sodium stearyl sulfate 77…”

Section: Chlorhexidinementioning

confidence: 99%

“…Arginine-nonyl ester 41 Idarubicin Dextran sulfate 95 Warm wax microemulsion solvent evaporation 95 Homogenization and stabilization with SDS 53 Dimyristoyl phosphatidyl glycerol 42 SNEDDS 42 Oleic acid 58,102,162 S/O/W emulsion 58 PLGA NPs by emulsion solvent diffusion 102,162 Pamoic acid disodium 165 SEDDS 165 Sodium laurate 165 Sodium stearoyl glutamate 165 Sodium deoxycholate 80,93,165 PLGA NPs by emulsion solvent diffusion 93 S/O/W emulsion 80 SEDDS 165 Sodium docusate 84,86 SEDDS 86 Stearic acid coacervation 84 Sodium dodecyl sulfate 49,84,111,177,178 Stearic acid coacervation 84 PLGA NPs by emulsion solvent diffusion 111,177,178 Electrospray with stearic or pamoic acid 49 Irinotecan Sodium docusate 98 Sodium stearyl sulfate 98 Taurocholic acid 98…”

Section: Doxorubicinmentioning

confidence: 99%

“…For peptide and protein drugs with many ionizable groups, the isoelectric point pI is a straightforward parameter to use, rather than trying to account for the pK a and ionizable state of each charged residue. As in charged polymers, the curve of 56 Sodium dodecyl sulfate 56 Taurocholic acid 56 Retinoic acid Benethamine 65,108,115 Hot melt homogenization using ultrasound emulsication [41][42][43]65,108,115 Laurylamine 46,107,114 Maprotiline (both HCl and free base) 115 Stearylamine 46,65,107,114 Triethylamine 46,65,107,114 Rose bengal Tetrabutylammonium bromide 66 Encapsulated into polystyrene microparticles using compressed carbon dioxide to plasticize polystyrene MPs and allow diffusion in 66 Tetrahexylammonium bromide 66 Tetraoctylammonium bromide 66 Salmon calcitonin 3.4 kDa peptide, 32 residues, pI: 8.86…”

Section: Leuprolidementioning

confidence: 99%

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Hydrophobic ion pairing: encapsulating small molecules, peptides, and proteins into nanocarriers

2019

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Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Jörgensen

Wibel

Bernkop‐Schnürch

2023

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The use of cationic and ionizable cationic lipids in pharmaceutical products, however, is a double-edged sword, as these excipients are of considerable safety concerns. Because of their permanent or pHdependent cationic nature, they perturbate cellular and nuclear membranes, trigger the release of degrading enzymes from lysosomes, cause mitochondrial permeabilization and dysfunction, generate reactive oxygen species (ROS), alter cytoplasmatic enzyme functions, and damage DNA. [3] To address this substantial shortcoming of cationic and ionizable cationic lipids, biodegradable alternatives have been introduced that are rapidly degraded in vivo to preferably endogenous metabolites. The design of such lipids is inspired by natural cationic or ionizable cationic compounds like arginine, lysine or betaine that are generally regarded as safe. Their conjugation to endogenous lipids like fatty acids or cholesterol results in amphiphilic lipids. As ester and amide bonds are cleaved in vivo by numerous enzymes such as lipases, esterases, and proteases, they are the preferred linkages between these natural building blocks.Since the FDA approved ethyl Nα-lauroyl-l-arginate as biodegradable food preservative being effective against a broad range of Gram-positive and Gram-negative bacteria, yeasts, and molds in 2005, [4] the potential use of biodegradable cationic and ionizable cationic lipids as pharmaceutical excipients has been evaluated by numerous research groups. As these excipients exhibit the same properties as their non-biodegradable counterparts but causing relatively low adverse effects, they will likely substitute currently used non-biodegradable lipids in the future. Within this review, we provide an overview on the different types of biodegradable cationic and ionizable cationic lipids, their synthesis and cleavage by endogenous enzymes. Applications in drug delivery systems and as antimicrobial agents are discussed. A guideline on their design and application is provided and an outlook on future developments is given. Building Blocks and Formation of Cationic and Ionizable Cationic LipidsGenerally, biodegradable cationic and ionizable cationic lipids are composed of biocompatible building blocks that are conjugated via a linkage such as an ester or amide bond. [5] Representative building blocks and linkages are depicted in Figure 1. Endogenous enzymes can break these linkages and degrade Cationic and ionizable cationic lipids are broadly applied as auxiliary agents, but their use is associated with adverse effects. If these excipients are rapidly degraded to endogenously occurring metabolites such as amino acids and fatty acids, their toxic potential can be minimized. So far, synthesized and evaluated biodegradable cationic and ionizable cationic lipids already showed promising results in terms of functionality and safety. Within this review, an overview about the different types of such biodegradable lipids, the available building blocks, their synthesis and cleavage by endogenous enzymes is provided. Moreover, ...

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Arginine-based cationic surfactants: Biodegradable auxiliary agents for the formation of hydrophobic ion pairs with hydrophilic macromolecular drugs

Cited by 39 publications

References 33 publications

Less Reactive Thiol Ligands: Key towards Highly Mucoadhesive Drug Delivery Systems

Less Reactive Thiol Ligands: Key towards Highly Mucoadhesive Drug Delivery Systems

Hydrophobic ion pairing: encapsulating small molecules, peptides, and proteins into nanocarriers

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

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