About the impact of superassociation of hydrophobic ion pairs on membrane permeability

Shahzadi, Iram; Phan, Thi Nhu Quynh; Bernkop‐Schnürch, Andreas

doi:10.1016/j.ejpb.2020.03.016

Cited by 16 publications

(11 citation statements)

References 36 publications

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“…Comparatively, the hydrophobic nature was enhanced outside the cavities, which could improve the nonpolar membrane permeability of the FPV-PP salt. 55,64,65 Usually, it is difficult to improve permeability and solubility simultaneously. 56 However, there are some examples that the solubility and permeability of cocrystals or salts were simultaneously improved: for example, the amantadine acetazolamide− piperazine salt 55 and the amantadine hydrochloride−sulfathiazole cocrystal.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The permeability of an API is affected by many factors, such as polarity, solubility, and size. , Hence, the enhanced permeability of FPV-PP may be explained by its high solubility and special cavity crystal structure which change the polarity of FPV. ,, Due to the high solubility of FPV-PP, the concentration gradients of FPV across the PAMPA membrane are built up quickly and effectively actuate the permeating action. , As described above, the special cavity structure of FPV-PP contains the primary polar functional groups stretching inward. Comparatively, the hydrophobic nature was enhanced outside the cavities, which could improve the nonpolar membrane permeability of the FPV-PP salt. ,, Usually, it is difficult to improve permeability and solubility simultaneously . However, there are some examples that the solubility and permeability of cocrystals or salts were simultaneously improved: for example, the amantadine acetazolamide–piperazine salt and the amantadine hydrochloride–sulfathiazole cocrystal .…”

Section: Resultsmentioning

confidence: 99%

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Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Wang

Yao

et al. 2021

Crystal Growth & Design

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Recently, favipiravir, as a broad-spectrum antiviral drug, has gain more attention because it might be a candidate to remedy the coronavirus disease 2019 (COVID-19). To improve its poor permeability and tabletability, four multicomponent crystals of favipiravir (FPV) were prepared by a slow evaporation or liquidassisted grinding method, including three cocrystals (FPVtheophylline, 1:1; FPV-saccharin, 1:1; FPV-5-fluorouracil, 1:1) and one salt (FPV-piperazine, 2:1). All of the crystal structures were solved by single-crystal X-ray diffraction. Interestingly, FPVtheophylline has a crystal structure similar to that of FPV, leading to similar properties, such as solubility, permeability, and tabletability. Except for FPV-theophylline, all of the other multicomponent crystals exhibit an enhanced permeability and tabletability. Our studies provide a new insight in overcoming the shortcomings of the important antiviral drug FPV.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Wang

Yao

et al. 2021

Crystal Growth & Design

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“…Previous studies, including our own recently published paper, showed that counterions in lipophilic salts or ILs can considerably alter the in vitro activity of drugs. , Surprisingly, the docusate-based ILs showed a 2- to 4-fold potentiation of in vitro antifungal activity (IC 90 ) against both a reference and clinical strain of C. neoformans . As the docusate anion was not active against C. neoformans in vitro at a concentration of 5 μM, the potentiation of activity observed in the docusate-based ILs is likely due to the permeation enhancing effect of docusate, − leading to increased uptake of the benzimidazoles by C. neoformans in vitro . Further studies are necessary to confirm this observation.…”

Section: Discussionmentioning

confidence: 98%

“…The transformation of hydrophobic and weakly basic drugs into ILs has emerged as a pharmaceutically viable strategy to improve the loading of drugs into lipid-based vehicles and eventually their oral bioavailability. Sodium docusate, an FDA-approved amphiphile capable of improving the permeation of molecules across biological membranes, − has been used as a counterion for the synthesis of pharmaceutical ILs of basic drugs. − , Hence, we evaluated the feasibility of developing docusate-based ILs.…”

Section: Discussionmentioning

confidence: 99%

Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and in Vitro Activity against Cryptococcus neoformans

et al. 2021

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As the existing therapeutic modalities for the treatment of cryptococcal meningitis (CM) have suboptimal efficacy, repurposing existing drugs for the treatment of CM is of great interest. The FDA-approved anthelmintic benzimidazoles, albendazole, mebendazole, and flubendazole, have demonstrated potent but variable in vitro activity against Cryptococcus neoformans, the predominant fungal species responsible for CM. We performed molecular docking studies to ascertain the interaction of albendazole, mebendazole, and flubendazole with a C. neoformans β-tubulin structure, which revealed differential binding interactions and explained the different in vitro efficacies reported previously and observed in this investigation. Despite their promising in vitro efficacy, the repurposing of anthelmintic benzimidazoles for oral CM therapy is significantly hampered due to their high crystallinity, poor pharmaceutical processability, low and pH-dependent solubility, and drug precipitation upon entering the intestine, all of which result in low and variable oral bioavailability. Here, we demonstrate that the anthelmintic benzimidazoles can be transformed into partially amorphous low-melting ionic liquids (ILs) with a simple metathesis reaction using amphiphilic sodium docusate as a counterion. In vitro efficacy studies on a laboratory reference and a clinical isolate of C. neoformans showed 2-to 4-fold lower IC 90 values for docusate-based ILs compared to the pure anthelmintic benzimidazoles. Furthermore, using a C. neoformans strain with green fluorescent protein (GFP)-tagged β-tubulin and albendazole and its docusate IL as model candidates, we showed that the benzimidazoles and their ILs reduce the viability of C. neoformans by interfering with its microtubule assembly. Unlike pure anthelmintic benzimidazoles, the docusate-based ILs showed excellent solubility in organic solvents and >30-fold higher solubility in bioavailability-enhancing lipid vehicles. Finally, the docusate ILs were successfully incorporated into SoluPlus, a self-assembling biodegradable polymer, which upon dilution with water formed polymeric micelles with a size of <100 nm. Thus, the development of docusate-based ILs represents an effective approach to improve the physicochemical properties and potency of anthelmintic benzimidazoles to facilitate their repurposing and preclinical development for CM therapy.

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“…Sodium dodecyl sulfate (SDS) was used as a lipophilic counter ion to increase the lipophilicity of insulin. SDS was chosen because of its sulfate moiety as sulfonate and sulfate groups were found to be superior over carboxylate groups regarding precipitation efficiency and stability of resulting ionic complexes [ 19 ]. INS-SDS complex was formed at various INS to SDS molar ratios ranging from 1:2 to 1:10.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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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 Poctanol/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.

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About the impact of superassociation of hydrophobic ion pairs on membrane permeability

Cited by 16 publications

References 36 publications

Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and in Vitro Activity against Cryptococcus neoformans

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

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