pH of anti-VEGF agents in the human vitreous: low impact of very different formulations

Abstract

Background The aim of the study was to measure pH changes of the human vitreous caused by the intravitreal drugs bevacizumab, ranibizumab, aflibercept, and ziv-aflibercept.MethodsFresh human vitreous samples were obtained during core vitrectomy (23-gauge) from patients with epiretinal gliosis. Aliquots of bevacizumab, ranibizumab, aflibercept or ziv-aflibercept (2 µl) were added consecutively to 200 µl of vitreous samples or 0.9% NaCl saline. The pH was measured using a pH-sensitive microelectrode. Rituximab, in off-label use against intraocular lymphoma, was tested as an IgG1 antibody.ResultsThe pH of the administered drugs was 5.91 for bevacizumab (95% CI 5.63–6.19), 5.32 for ranibizumab (95% CI 5.0–5.63), 6.05 for aflibercept (95% CI 5.78–6.31), ziv-aflibercept 6.1 (95% CI 6.05–6.15), and 6.29 for rituximab (95% CI 5.97–6.61). While the fresh and undiluted vitreous fluid showed pH values of 7.0–7.4, pH values increased if saline or rituximab were added. In contrast, the pH decreased slightly if aflibercept, bevacizumab, ranibizumab or ziv-aflibercept were supplemented. The observed pH decreases were not significant after ranibizumab was added. Significant changes were only notable with higher-than-normal amounts of bevacizumab (26–40 µl). The vitreous showed the most robust buffering capacity towards ranibizumab and rituximab.ConclusionsThe pH changes in vitreous samples elicited by the usual intravitreal anti-VEGF drugs differed clearly, but only by much higher concentrations than used in the clinical routine. Although the ingredient solution of ranibizumab showed the lowest pH, it caused only moderate changes of vitreal pH compared to bevacizumab, aflibercept or ziv-aflibercept.

Tolerability Assessment of Formulation pH in New Zealand White Rabbits Following Intravitreal Administration

“…We included histidine chloride pH 5.5 buffer as a control since clinical tolerability data can be cross-referenced for this formulation. 2 Here we show that all buffers in the pH 4.0 to 5.5 range were well tolerated and did not cause inflammation, intraocular pressure (IOP) changes, or gross or microscopic findings in any eye.…”

“…The current nonclinical and clinical data suggest that pH 5.5 to 7.4 is an acceptable range for intravitreally administered drugs. 1,2 The pH of the drug product is an important manufacturability parameter as it generally affects drug properties as well as shelf life. It is desirable to avoid extreme pH conditions and formulate drugs close to the physiological vitreous pH in order to limit the disruption of the ocular environment.…”

Thermo-Responsive PLGA-PEG-PLGA Hydrogels as Novel Injectable Platforms for Neuroprotective Combined Therapies in the Treatment of Retinal Degenerative Diseases

“…Besides, GPC peaks and PDI for both copolymers 1 and 2 (1.22 and 1.36) showed low polydispersity, uniformity and a unimodal distribution. One important aspect in the development of preparations for intravitreal administration is the resultant pH, in order to avoid any harmful effects due to pH deviation from physiological values [ 40 ]. Some studies have previously described the use of different aqueous vehicles like acetate buffer [ 41 ], water [ 42 ] or sodium chloride (NaCl) to prepare PLGA-PEG-PLGA based hydrogel formulations.…”

Assessment of patient pain experience during intravitreal ranibizumab and aflibercept injection

“…However, studies have shown that this pH difference is easily buffered by the vitreous after intravitreal injection. [26] Furthermore, the retina has no nociceptor and sensory innervation to feel the pain related to pH changes. [27] The pain felt during injection is thought to be felt through scleral sensory nerves.…”