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Stability of an ophthalmic formulation of polyhexamethylene biguanide in gamma-sterilized and ethylene oxide sterilized low density polyethylene multidose eyedroppers.

ABSTRACT: Background:Polyhexamethylene biguanide (PHMB) eye drops are a frequently used medication to treat Acanthamoeba keratitis. In the absence of marketed PHMB eye drops, pharmacy-compounding units are needed to prepare this much needed treatment, but the lack of validated PHMB stability data severely limits their conservation by imposing short expiration dates after preparation. In this study we aim to assess the physicochemical and microbiological stability of a 0.2 mg/mL PHMB eye drop formulation stored in two kinds of polyethylene bottles at two different temperatures. Methods:A liquid chromatography coupled with diode array detector stability-indicating method was validated to quantify PHMB, using a cyanopropyl bonded phase (Agilent Zorbax Eclipse XDB-CN column 4.6 × 75 mm with particle size of 3.5 ?m) and isocratic elution consisting of acetonitrile/deionized water (3/97 v/v) at a flow rate of 1.3 mL/min. PHMB eye drops stability was assessed for 90 days of storage at 5 and 25 °C in ethylene oxide sterilized low density polyethylene (EOS-LDPE) and gamma sterilized low density polyethylene (GS-LDPE) bottles. The following analyses were performed: visual inspection, PHMB quantification and breakdown products (BPs) screening, osmolality and pH measurements, and sterility assessment. PHMB quantification and BP screening was also performed on the drops emitted from the multidose eyedroppers to simulate in-use condition. Results:The analytical method developed meets all the qualitative and quantitative criteria for validation with an acceptable accuracy and good linearity, and is stability indicating. During 90 days of storage, no significant decrease of PHMB concentration was found compared to initial concentration in all stored PHMB eye drops. However, BP were found at day 30 and at day 90 of monitoring in both kind of bottles, stored at 5 and 25 °C, respectively. Although no significant variation of osmolality was found and sterility was maintained during 90 days of monitoring, a significant decrease of pH in GS-LDPE PHMB eye drops was noticed reaching 4 and 4.6 at 25 °C and 5 °C respectively, compared to initial pH of 6.16. Discussion:Although no significant decrease in PHMB concentration was found during 90 days of monitoring in all conditions, the appearance of BPs and their unknown toxicities let us believe that 0.2 mg/mL PHMB solution should be conserved for no longer than 60 days in EOS-LDPE bottles at 25 °C.

SUBMITTER: Bouattour Y

PROVIDER: S-EPMC5910790 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Stability of an ophthalmic formulation of polyhexamethylene biguanide in gamma-sterilized and ethylene oxide sterilized low density polyethylene multidose eyedroppers.

Bouattour Yassine Y Chennell Philip P Wasiak Mathieu M Jouannet Mireille M Sautou Valérie V

PeerJ 20180418

<h4>Background</h4>Polyhexamethylene biguanide (PHMB) eye drops are a frequently used medication to treat Acanthamoeba keratitis. In the absence of marketed PHMB eye drops, pharmacy-compounding units are needed to prepare this much needed treatment, but the lack of validated PHMB stability data severely limits their conservation by imposing short expiration dates after preparation. In this study we aim to assess the physicochemical and microbiological stability of a 0.2 mg/mL PHMB eye drop formu ...[more]

PMID: 29682408

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Project description:Antimicrobial resistance is a critical public health issue that requires a thorough understanding of the factors that influence the selection and spread of antibiotic-resistant bacteria. Biocides, which are widely used in cleaning and disinfection procedures in a variety of settings, may contribute to this resistance by inducing similar defense mechanisms in bacteria against both biocides and antibiotics. However, the strategies used by bacteria to adapt and develop cross-resistance remain poorly understood, particularly within biofilms -a widespread bacterial habitat that significantly influences bacterial tolerance and adaptive strategies. Using a combination of adaptive laboratory evolution experiments, genomic and RT-qPCR analyses, and biofilm structural characterization using confocal microscopy, we investigated in this study how Escherichia coli biofilms adapted after 28 days of exposure to three biocidal active substances and the effects on cross-resistance to antibiotics. Interestingly, polyhexamethylene biguanide (PHMB) exposure led to an increase of gentamicin resistance (GenR) phenotypes in biofilms formed by most of the seven E. coli strains tested. Nevertheless, most variants that emerged under biocidal conditions did not retain the GenR phenotype after removal of antimicrobial stress, suggesting a transient adaptation (adaptive resistance). The whole genome sequencing of variants with stable GenR phenotypes revealed recurrent mutations in genes associated with cellular respiration, including cytochrome oxidase (cydA, cyoC) and ATP synthase (atpG). RT-qPCR analysis revealed an induction of gene expression associated with biofilm matrix production (especially curli synthesis), stress responses, active and passive transport and cell respiration during PHMB exposure, providing insight into potential physiological responses associated with adaptive crossresistance. In addition, confocal laser scanning microscopy (CLSM) observations demonstrated a global effect of PHMB on biofilm architectures and compositions formed by most E. coli strains, with the appearance of dense cellular clusters after a 24h-exposure. In conclusion, our results showed that the PHMB exposure stimulated the emergence of an adaptive cross-resistance to gentamicin in biofilms, likely induced through the activation of physiological responses and biofilm structural modulations altering gradients and microenvironmental conditions in the biological edifice.

Dataset Information

Stability of an ophthalmic formulation of polyhexamethylene biguanide in gamma-sterilized and ethylene oxide sterilized low density polyethylene multidose eyedroppers.

Publications

Stability of an ophthalmic formulation of polyhexamethylene biguanide in gamma-sterilized and ethylene oxide sterilized low density polyethylene multidose eyedroppers.

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