Skin care has rapidly evolved as a concept over the last decade. Formulators in this field have worked tirelessly to bring topical solutions to market that effectively treat skin-related maladies, safely and consistently. In fact, a number of different active pharmaceutical ingredients (APIs) and biologics have been introduced during this time, from retinol and hyaluronic acid, to recent breakthroughs in topical probiotic and synbiotic technology.
The convergence of skin healthcare and beauty over the years has culminated in the creation of a new market space: cosmeceuticals, which aim to treat skin conditions instead of merely covering them up. As the name implies, these treatments go beyond the cosmetic to deliver APIs or other small molecules directly on or just beneath the skin. The products’ unique ability to elevate aesthetics as they treat physical ailments - like texture, scarring, aging effects, redness and more - makes them very popular across a wide range of demographics, suggesting an opportunity for formulators to ride this trend to market success.
However, this overlap of product functionality - the cosmetic and the therapeutic - brings with it a similar overlap between companies in very different fields: pharmaceutical manufacturers and personal care brands. There’s no doubt that these different perspectives have played off one another to create exciting new products and business opportunities. But what about formulators or brands that may be new to the concept of topical drug delivery? Knowledge gaps such as these are common for brands on the outside of pharma looking to capitalize on this popular trend.
By partnering with the right ingredient supplier - one equipped with both pharmaceutical expertise and materials design capabilities - brands that are new to the concept may achieve significant breakthroughs in the realm of cosmeceuticals. It all comes down to understanding the behavior of topical formulations, a knowledge base that can only be attained through extensive lab testing.
DuPont Nutrition & Biosciences (DuPont) has conducted research that may provide guidance for ushering formulators and brands through the process of advancing topical drug delivery through the study of rheology. No doubt valuable in the realm of topical pharmaceuticals, the findings in turn may enable new formulations in the growing field of cosmeceuticals.
The Science Behind the Sensation
As topical treatments have advanced, so too has DuPont conducted experiments and made adjustments to help customers evolve at a commensurate rate. Several excipients and APIs like the ones offered by DuPont have been used in the personal care space for years. Most recently, our examination of the rheology of a topical pain medication diclofenac shows how ingredients and manufacturing processes can be optimized for topical solutions as a whole, which include cosmeceuticals.
Research began after considering the topical drug delivery of cellulosics commonly used in oral suspensions, nasal sprays and other delivery formats. Spurred by frequent customer requests for assistance in understanding the rheology of our polymers, a team of DuPont researchers based in Hyderabad, India, began the process of examining our excipients and how they enable topical drug delivery formulations.
After looking at different excipients and how they affected the stability of APIs, the team garnered a greater, more formal understanding of how to characterize these formulations. And as a result, DuPont has discovered a helpful methodology in the development of topical drug delivery formats.
Rheology at a Glance
Semi-solid topical formulations such as gels and ointments are dosage forms that are applied to skin for local delivery of APIs. Diclofenac topical gel formulations are non-steroidal anti-inflammatory drugs (NSAIDs) widely used in pain management. Topical gels offer several advantages over oral dosage forms, including the convenience of local application and the prevention of side effects from systemic delivery. It’s also important to note that topical formulations undergo a wide variety of stressors during manufacturing, packaging and even dispensing the product from the tube, all of which can affect the product’s ability to remain on the skin long enough to ensure efficacy.
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This is why formulators need to characterize any and all rheological properties of a topical solution, as rheology provides information on a formulation’s ability to spread over skin and mucosae – the main determinant of performance. The formulation’s rheological characteristic depends on the microstructure of the product, which may be affected by manufacturing conditions. Over the course of DuPont’s study, researchers set out to establish a testing procedure to investigate rheological properties of the diclofenac topical gel formulations like yield stress, viscoelastic behavior and viscosity at different shear rates. As a result, different rheological methods were established to understand properties of the diclofenac gel products like viscosity, viscoelastic behavior, yield stress and effect of temperature sweep.1
Research focused on four different commercial formulations of diclofenac topical gels, all procured from a local pharmacy. The studies were conducted using the following equipment: a TA Instruments DHR3 Rheometer, which incorporated a Peltier plate with its temperature set at 25°C using 60 mm stainless steel geometry with a gap of 800 μm between the lower plate and upper plate maintained for the sample. Figures 1 – 5 give a general overview of the results found over the course of the study.
The viscoelastic behavior of formulations was studied by subjecting samples to oscillation strain sweeps in the range of 0.01% to 500%. Researchers went with a shear rate in the range of 0.01 to 100 (1/s) when using the flow sweep method to determine viscosity. In conducting the time sweep study, researchers found that by changing the strain from 0.5% to 50% and back, they garnered a better understanding of product behavior and the ability to achieve a steady state, which is crucial for performance. Finally, regarding the oscillation temperature sweep study, DuPont’s experts stayed within the range of 15°C to 45°C to understand the effect of temperature on the product stability.
All formulations showed viscoelastic behavior with storage modulus higher than loss modulus, as shown in Table 1, which indicates that the microstructure of a given formulation is highly organized. As expected, phase angle values indicated that the gels were viscous enough to allow for spreading and rubbing on the skin. Each formulation also exhibited shear-thinning properties, suggesting product viscosity reduces in order to allow spreading across the skin. All formulations showed an ability to break down its structure and rebuild after removing the strain, indicating that each of them was able to stay on the skin at the point of application without continuing to flow.
So, What’s the Point (of Impact)?
One of the biggest takeaways from the study was the importance of the rheometer as a tool for investigating topical gel behavior. By understanding and measuring rheology in this way, formulators can in turn begin to predict the performance of formulations during processing, packaging, dispensing, stability, and spreadability across the skin - these findings have wide-reaching implications for not just the larger fi eld of topical medications, but the rising trend of cosmeceuticals as well. Introducing new products to the cosmeceutical market - not to mention the broader arena of topical solutions – is much easier if performance can be effectively gauged beforehand, from product development to application.
The general findings of the study were promising for a few reasons. First, the rheological evaluation of topical gel formulation provided information on spreadability of the formulations upon application to the skin through yield stress and viscosity determination. But the oscillation strain experiments also provided insight into the microstructure of the formulations, and temperature sweep studies provided information on stability.
The findings of the DuPont India team help us understand how important rheology is to formulations beyond just pain medication. Many poorly water-soluble APIs tend to crystalize and come out of solution, rendering them unavailable to the skin. The results of the study point to the behavior of excipients not just as delivery mechanisms, but also as stabilizing agents, which bolster the efficacy of APIs.
Conclusions
By paying special attention to the rheology of topical formulations, pharmaceutical manufacturers can develop new topical formulations for the pharmaceutical and cosmeceutical markets. These tools can enable formulators to understand if an API is behaving in a consistent, reproducible way while in suspension and if the formulation will have the right application properties. However, many companies looking to enter the arena of skin healthcare may lack the expertise in these techniques. Therefore, having the right supplier with extensive pharmaceutical and materials expertise can open the door for new players and products in the wider topical and niche cosmeceutical spaces.
References
- Y.S.R. Krishnaiah et al., International journal of Pharmaceutics, 475 (2014), 110-122