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

Abstract

BackgroundPolyhexamethylene 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.MethodsA 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 μm) 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.ResultsThe 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.DiscussionAlthough 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.

Stability of Ophthalmic Atropine Solutions for Child Myopia Control

“…However, this could decrease ophthalmic tolerance, especially for paediatric patients, which is the target population for which these formulations are designed. In the formulations we tested, the pH was buffered to a more physiological value (around pH 6), thus hopefully limiting potential unpleasantness for the children during administration and therefore increasing therefore adherence to treatment as well as suppressing any potential modifications of pH that have already been reported during the use of gamma-sterilized LDPE eyedroppers [ 28 ].…”

“…Indeed, few studies have been published concerning atropine eyedrops stability, but the analyses were either lacking several tests or suffered from shortcomings concerning breakdown product research [ 24 , 25 , 26 ]. As single-dose container technology is not readily available to compounding pharmacies, multidose eyedroppers (often in low dose polypropylene) are the most used container and therefore the most studied [ 27 , 28 , 29 , 30 ]. However, not all of those devices possess a system allowing their content to be preservative-free, and their contents must therefore be preserved.…”

Cyclodextrins Allow the Combination of Incompatible Vancomycin and Ceftazidime into an Ophthalmic Formulation for the Treatment of Bacterial Keratitis

“…If the affinity of this form of VA is higher for CZ than for HPCD, it would preferentially associate with CZ and precipitate instead of being complexed by the HPβCD. In addition, it has been shown that an interaction is possible between the contents and the container for some LDPE packaging articles sterilized with gamma rays, leading to acidification of the eye drops [ 57 ]; in our case, this acidification could lead us below our pH limit and therefore lead to precipitation if the buffering capacity is exceeded.…”

Preparation and Antifouling Property of Polyurethane Film Modified by PHMG and HA Using Layer-by-Layer Assembly

“…The effective antibacterial activity of PU-PHMG was attributed to the bactericidal capacity of PHMG. The interaction between PHMG and the anionic components of bacterial cell wall compromises membrane integrity, further causing cell membrane rupture and leads to microbial death [ 53 , 54 ]. The inhibition rates of PU-(PHMG/HA) 5 /5-5 on E. coli , P. aeruginosa , and S. aureus were 99.99%, 99.96%, and 99.99%, respectively, indicating that the film had outstanding antibacterial activity.…”