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New Classes of Polycationic Compounds as Preservatives for Ophthalmic Formulations

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Abstract

Purpose

The purpose of this research work was to develop new polycationic compounds based on pyridine and piperidine structures with high antimicrobial activities against bacteria and fungi. Furthermore, the compounds should offer a lower toxicity than the commonly used preservatives for ophthalmic formulations, such as benzalkonium chloride (BAC) and polyquaternium-1 (PQ1).

Methods

Two polymers and three dimeric compounds were developed. Minimum inhibitory concentrations were determined for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis. The compounds were characterized regarding their impact on cell viability, cytotoxicity, epithelial integrity and surface tension. MTT and CytoTox-Glo™ assays, permeation studies with mannitol and transepithelial electrical resistance (TEER) measurements were performed on human corneal epithelial or MDCK I cells. BAC and PQ1 were used as references.

Results

Three polycationic compounds exhibited high antimicrobial activity against the tested microorganisms comparable to that of BAC. Four compounds were tolerated as well as or better than PQ1. In addition, the TEER, permeability and surface tension were only affected by compounds with amphiphilic properties.

Conclusion

The pyridine- and piperidine-based polycationic compounds are promising candidates as new preservatives for ophthalmic formulations. Their high antimicrobial efficacy and good tolerability indicate a different mechanism of action compared to BAC.

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Abbreviations

BAC:

Benzalkonium chloride

cfu:

Colony forming unit

DiPy:

Dimer with dipyridine motif

DiPyC10:

Dimer with dipyridine motif and C10 alkyl chain in the end group

DiPyC12:

Dimer with dipyridine motif and C12 alkyl chain in the end group

GPC:

Gel permeation chromatography

HCE-T:

Human corneal epithelial cells

KRB:

Krebs-Ringer buffer

log P:

logarithmic partition coefficient

MDCK I:

Madin-Darby canine kidney cells

MHB:

Mueller-Hinton broth

MIC:

Minimum inhibitory concentration

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PDA:

Potato dextrose agar

PolyPi:

Polymer with dipiperidine motif

PolyPy:

Polymer with dipyridine motif

PQ1:

Polyquaternium-1

SDA:

Sabouraud dextrose agar

SD:

Standard deviation

TEER:

Transepithelial electrical resistance

TSA:

Tryptic soy agar

TSB:

Tryptic soy broth

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Authors and Affiliations

  1. Institut für Pharmazeutische Technologie, Technische Universität Braunschweig, Braunschweig, Germany

    Dörte von Deylen & Stephan Reichl

  2. ChiroBlock GmbH, Wolfen, Germany

    Christina Dreher & Oliver Seidelmann

Authors
  1. Dörte von Deylen
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  2. Christina Dreher
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  3. Oliver Seidelmann
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  4. Stephan Reichl
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Corresponding author

Correspondence to Stephan Reichl.

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Guest Editors: Hovhannes J Gukasyan, Shumet Hailu, and Thomas Karami

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von Deylen, D., Dreher, C., Seidelmann, O. et al. New Classes of Polycationic Compounds as Preservatives for Ophthalmic Formulations. Pharm Res 36, 11 (2019). https://doi.org/10.1007/s11095-018-2536-9

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