Category: Formulation and Quality
Purpose: Alginates form much stronger gels when cross linked by divalent cations (e.g., Ca++) than when aggregated in the presence of the monovalent cations (e.g., Na+) that are at much higher concentrations in the tear fluid. Previous work indicated that Ca++ can be displaced from Calcium Gluconate (CaG) by monovalent cations that are predominant in tear fluid. Alginate solutions with incorporated CaG were shown to demonstrate promise as ocular gel forming solutions (GFS). That is, they appear able to form in situ gels when exposed to tear fluid. The data also indicated that CaG can be used to improve the use of alginate for slowing drug release. The purpose of this study was to examine the ocular in situ gelling properties when Calcium Glycerol Phosphate (CaGP) is used as a calcium source as compared to CaG.
Methods: Screening preparations were manufactured in order to determine optimal concentrations of alginate and CaGP or alginate and CaG. Multiple repeat samples of selected alginate formulations of CaGP or CaG were prepared in order to enable statistical analysis (ANOVA followed by Tuckey’s post hoc). The shear stress sweep viscosities of the samples were measured using a rotational viscometer. Viscosities of the sample formulations were measured at room (ambient) temperature to mimic patient storage and at eye temperature to forecast the strength of the formed gel after administration to the eye. At eye temperature, the alginate-CaG solutions were combined in a 5:1 ratio with simulated tear fluid (STF) to more accurately simulate the eye environment after administration of an eye drop. Viscosities are expressed in cP and as the mathematical model fit constant K, which is the projected viscosity at a shear rate of 1 sec-1.
Results: A change in CaG concentration (1% alginate) from 0.25% to 0.27% resulted in a packaging viscosity increase of 4,856 cP (statistically significant). An increase to 0.157% CaGP from 0.145% resulted in the same overall percent increase as an increase of 0.27% CaG from 0.25% CaG. In comparing the two Ca++ providing molecules, a change in CaGP concentration (1.5% alginate) from 0.145% to 0.157% results in a packaging viscosity increase of 1265 cP (not statistically significant). It appears that packaging viscosities for alginate based formulations are less sensitive to slight changes in CaGP concentrations as compared to slight changes in CaG concentrations. The average eye viscosity for the 1% alginate plus 0.25% CaG formulation was 20,504 cP. The average eye viscosity for the 1.5% alginate plus 0.145% CaGP formulation was 76,502 cP. The difference in eye viscosity is statistically significant at the < 0.0001 level. The average packaging viscosity for the 1% alginate plus 0.25% CaG formulation was 2,497 cP. The average packaging viscosity for the 1.5% alginate plus 0.145% CaGP formulation was 3,048 cP. There is no statistical difference between these values. Previous experimentation indicated that a packaging viscosity of 5,000 cP is a good upper limit to ensure that patients can easily administer a formulation as an eye drop. These results indicate that there is no advantage to using CaG rather than CaGP in regard to packaging concerns, but there should be a significant improvement in ocular retention when using CaGP.
Conclusion: The addition of both CaGP and CaG to alginate results in formulations demonstrating stronger gels when added to STF than alginate alone and may be applied via eyedropper. The results generated in this study indicate that CaGP is superior to CaG when being used as a Ca++ source for alginate based GFS.