A rundown on the benefits of opting for an orthogonal characterisation strategy for micro-emulsions and the offerings from Malvern to make it possible
The increasing use of use of microemulsions, such as cyclosporines, as the API in ophthalmic emulsions is a result of specific material properties, such as stability, low surface tension, and small droplet size. These features are responsible for ocular absorption and the retention of the drug in the eye, parameters on which the duration of action of the drug depends.
The formulation of ophthalmic emulsions (eye drops) with long shelf lives is complicated by the tendency to aggregate, particularly in the presence of the polymers that are used to increase formulation stability. Such complex formulation conditions also impart unique rheological characteristics to ophthalmic emulsions, characteristics that have a major effect on the applicability of the drug. This is also the case for generic versions of microemulsions, due to the regulatory requirement that they conform to the same standards of quality, efficacy and safety as the innovator.
This article describes a comprehensive multi-parameter strategy for the characterisation of microemulsion stability, flow characteristics and particle size, used to improve the efficiency of the approval process for both innovative and generic ophthalmic emulsions.
The solution
The Malvern Zetasizer ZSP was used to characterise the zeta potential, using electrophoretic light scattering (ELS), of samples diluted 1/4 as per FDA guidance. Zeta potential measurements give assessment of microstructural stability, intermolecular repulsion meaning that formulations with larger zeta potential values are more electrostatically stable.
Size and polydispersity index (PDI) were also measured on the Zetasizer, using dynamic light scattering (DLS). Though such measurements are quick, simple, information rich and require very little sample, microemulsions often contain larger particles that are difficult to characterise using DLS. For this reason, use of laser diffraction as a complementary technique to calculate SPAN or D50 is advised.
Laser diffraction measurements (Figure 1) were carried out using a Malvern Mastersizer 3000 with the newly released Hydro SV small volume wet sample dispersion unit. The Hydro SV accessory reduces the sample requirements of laser diffraction dramatically, with only 5 ml of dispersant and 0.45 ml of sample was required for the cyclosporine measurements presented here.
Finally, in order to fully account for the dilution involved in the laser diffraction and zeta potential measurements described above, and to provide rheological analysis as per FDA guidance, analysis was performed using Malvern’s Kinexus rheometer (Figure 2). Viscosity profiling gives understanding of stability in terms of bulk flow (for instance, the likelihood of larger particles sedimenting), and allows quality and comparability assessments of samples under formulation conditions (without dilution).
Orthogonal assessment of stability, applicability, and efficacy
Table 1 shows that the both formulations have highly negative zeta potential values, suggesting that both samples are electrostatically stable (though the innovator Zeta Potential is twice as great as that of the generic). The innovator also gave a much larger Z-average size and polydispersity index (PDI) than the generic. DLS data suggested the presence of large particles which would be better characterised using laser diffraction analysis.
Figure 3 shows analysis of innovator (sample A) and generic (sample B) cyclosporine products using the Mastersizer 3000. Repeatability of D50 (and also D10 and D90) for each sample is excellent, so we can be sure that the differences in particle size distribution between the innovator and generic are real, with the innovator containing a greater quantity of > 200 nm particles.
Table 1: Particle Size Distribution analysis of innovator and generic Cyclosporines using Mastersizer 3000.
Figure 4 shows flow curves for the innovator and generic sample, measured using the Malvern Kinexus. Both materials demonstrate a similar shear-thinning trend, with viscosity decreasing with increasing shear rate. Such a quality is important for an ophthalmic emulsion, with high viscosity in the absence of force giving the sample stability during storage and a relatively long shelf-life, and lower viscosity upon application of force (such as squeezing of the container) making application of the drug to the eye much easier. Despite the similarity of the flow curve trends, at any given sheer rate the innovator is more viscous than the generic, suggesting that the likelihood of larger particles sedimenting in the generic is greater than in the innovator (all other things being equal).
Confidence in Your Product
By acquiring data using 4 different methods, we were able to perform a complete comparability study of stability, polydispersity, particle size and applicability of the drug, as per regulatory guidance. The innovator cyclosporine was more stable than the generic in terms of both electrostatic (probed with zeta potential) and sedimentation (assessed with Kinexus) stability. Despite this, the generic showed greater uniformity (lower PDI), the innovator containing more > 200 nm particles and a significant quantity of particles > 5 microns (as measured using the Mastersizer 3000). As always, the decision of regulatory authorities to give approval to a generic is dependent on how clinically relevant these differences are deemed to be.
In addition to providing an assessment of innovator-generic comparability without prior dilution, Malvern’s Kinexus system offers many other ways to characterise microemulsions. For instance, the effect of the blinking of a patient’s eye during application on the flow characteristics of the drug can be simulated by measuring using an appropriate shear rate range. Such data would give information on the applicability of the drug, a quality that is of concern to developers due to the difficulties of creating microemulsion formulations that fully permeate the eye.
In summary, this article demonstrates the reason behind regulatory emphasis on an orthogonal approach to micro emulsion characterisation, and the means that Malvern Instruments have developed to provide for such an approach.
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