Topical drug delivery has long been a significant route of treatment for various ailments. Ranging from simple salves used by ancient civilizations to the sophisticated formulations of today, the progress in this sector represents the confluence of biology, chemistry, and innovative technology. But the role of a drug isn't just about its therapeutic effect. The medium through which it's delivered – the excipients – play an indispensable role in dictating the efficacy, stability, and overall performance of a topical product.

In the world of pharmaceuticals, excipients are the unsung heroes; they can influence everything from the drug's penetration into the skin to its shelf life. They are central to research and development, ensuring that drug products are not only effective but also patient-friendly. This article dives into the transformative realm of excipients in topical drug delivery, uncovering technologies and a critical trend that is impacting today’s topical products.

Advanced Excipient Technologies

Modern research has unearthed a plethora of excipient technologies that enhance the efficacy, stability, and user-friendliness of topical formulations. For example:

1. Permeation Enhancers

Permeation enhancers are substances that promote drug absorption often by temporarily reducing the barrier function of the stratum corneum, the outermost layer of the skin, allowing for increased drug penetration into and through the skin. Some common permeation enhancers include:

Fatty Acids: These compounds, such as oleic acid and linoleic acid, have shown to increase the fluidity of lipids in the skin's outer layers, enhancing drug penetration. Studies indicate that formulations with certain fatty acids can increase drug permeation significantly.
Surfactants: These ingredients can be categorized into three classes - anionic, cationic, or nonionic. Their drug delivery enhancement is governed by several factors, such as the presence of functional groups, hydrocarbon chain length, the degree and position of unsaturation, and whether they are used alone or in combination.
Sulfoxides: Dimethyl sulfoxide (DMSO) is a prominent example known for its permeation-enhancing properties. Topical formulations with DMSO have been seen to enhance drug delivery rates by 70% or more in certain cases.¹

It is important to note, however, that patient side effects like irritation have been reported with some of these traditional permeation enhancers and, as such, alternative technologies have come into play, such as cyclodextrins or excipients that enable emulsions with liquid crystal structures to enhance drug delivery. Many of these are already present on the FDA’s Inactive Ingredient Database (IID).

2. Smart Polymers

Smart polymers are responsive materials that undergo significant, often reversible, changes in response to external stimuli like temperature, pH, or light.

Thermo-responsive Polymers: These polymers undergo gelation at body temperature, ensuring prolonged drug retention on the skin.
pH-responsive Polymers: Especially useful for diseased skin conditions with altered pH, these polymers can detect pH changes and release the drug accordingly.
Photo-responsive Polymers: Triggered by light, these polymers are being researched for controlled drug release.

3. Mucoadhesive Polymers

Mucoadhesion describes the attractive forces between a material and mucus or a mucous membrane. Mucus and mucous membranes are found in multiple areas of the human body, from the mouth, throat, and nasal cavity to parts of the eyes, rectum or vagina. For topical formulations intended to target these areas, mucoadhesive excipients are beneficial for effective drug delivery.

For an excipient to be mucoadhesive, it must be a synthetic or natural hydrophilic polymer containing functional groups that can interact with mucin glycoproteins. This interaction occurs via non-covalent bonds, such as hydrogen bonding, van der Waals forces, and ionic interactions. Example excipients include:

Carbomers (e.g., Carbopol^® polymers)
Carrageenan
Sodium carboxymethylcellulose (Na-CMC).

One study has shown that, compared to other materials (including carrageenan and Na-CMC), carbomers, specifically Carbopol^® polymers, provide the longest mucoadhesive retention over time, even after 30 minutes.²

4. Nano-encapsulation

By reducing the drug molecule's size to the nano level, it’s possible to overcome the skin's barrier and enhance penetration.

Liposomes and Niosomes: These lipid-based nanoparticles can increase drug stability and penetration.
Nano-emulsions: Water and oil-based nano-emulsions improve drug solubility and skin permeation,
Solid Lipid Nanoparticles (SLN): Offering a controlled release mechanism, SLN formulations can sustain drug release for extended periods, ensuring prolonged therapeutic effects.

Trend: Sensory & Improving Patient Compliance

One of the most significant challenges in the pharmaceutical landscape isn't just developing effective medicines, but ensuring patients use them correctly and consistently. Modern excipients, thus, play a pivotal role in ensuring topical drugs are not only potent but also patient-friendly. Here’s how the evolution of excipients is fostering greater patient compliance:

1. Texture and Aesthetics

The tactile sensation of a formulation can greatly influence a patient's willingness to use it. Poor adherence rates (40-70%) have been linked to product attributes, including poor cosmetic characteristics.³ The inclusion of certain types of ingredients that target enhanced sensory properties are a critical piece of enhancing topical patient compliance.

Emulsifiers: An emulsifier is an ingredient that stabilizes an emulsion. Non-ionic emulsifiers, such as Pemulen™ polymeric emulsifiers, in particular are considered non-irritant and provide optimal aesthetics, feel, and drug penetration.
Emollients: Emollients, such as Glucam™ P-20 distearate emollient, are used in topical preparations to impart lubrication, spreading ease, texture, and softening of the skin. They also counter the potentially drying or irritating effects of surfactants on the skin.
Humectants: A humectant is a substance that promotes the retention of moisture on the skin. Certain ingredients, such as Glucam™ humectants, deliver light, satiny after-feel to skin formulations and are effective at reducing the tack of glycerin. This increased moisture can also increase an active ingredient’s solubility, which can then in turn increase the skin penetration, further benefiting the patient.

2. Reduced Irritation

Formulation-induced skin irritation can significantly deter patients from continuing with a treatment and is a common cause of patient non-compliance to topical medicines.^4-6

Ceramides: These lipid molecules can replenish the skin's natural barrier, thus reducing the chances of irritation.
Vitamin E and its Derivatives: Acting as antioxidants, they can counteract potential oxidative stress from other ingredients,
Aloe Vera and Allantoin: Recognized for their soothing properties, these ingredients can mitigate irritation and enhance the skin's healing process.

3. Enhanced Drug Stability & Shelflife

A product's efficacy can be compromised if it degrades too quickly, which can lead to decreased patient trust and adherence.

Chelating Agents: Ingredients like EDTA can bind to metal ions that may accelerate degradation, ensuring a longer shelflife.
Antioxidants: Compounds like butylated hydroxytoluene (BHT) prevent oxidative degradation of sensitive ingredients, leading to formulations that remain effective for extended periods.
Ingredients That Do Not Promote Microbial Growth: Certain synthetic excipients, like carbomers, as supplied do not support mold or bacterial growth, resulting in a stable final product that patients can trust. Carbomers also impart a high yield value, which can permanently suspend drug particles in a formulation. This eliminates the need to mix or shake the final product, ensuring good shelf life.

The Bottom Line

Topicals today play an increasingly important role in first-line therapy, as they can have significant benefits over systemic routes of administration. However, with this enhanced importance comes amplified demands from consumers and the need for differentiation in a highly competitive market. Patients seeking topical products have high expectations regarding sensory and aesthetic properties, as well as the effectiveness of the drug, which influences the market and how formulators are making their products "stand out from the crowd". The best way to achieve these properties is through strategic selection of advanced excipient technologies that have proven performance and sensory optimization properties.

Learn more about top Topical Drug Delivery Trends in our recent webinar: 2024 Trends in Topical Drug Delivery: Insights & Innovation - Lubrizol

References:

Tarrand, J., LaSala, P., Han, X.-Y., & Kontoyiannis, D. (2012, May). Dimethyl Sulfoxide Enhances Effectiveness of Skin Antiseptics and Reduces Contamination Rates of Blood Cultures. National Library of Medicine. Retrieved January 19, 2024, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347107/
Rezak, A. & The Lubrizol Corporation. (n.d.). Mucoadhesive Polymers in Pharmaceutical Formulations. https://www.lubrizol.com/-/media/Lubrizol/Health/Literature/Mucoadhesive-Polymers-in-Pharmaceutical-Formulations.pdf. Retrieved January 18, 2024, from https://www.lubrizol.com/-/media/Lubrizol/Health/Literature/Mucoadhesive-Polymers-in-Pharmaceutical-Formulations.pdf
2017 study, published in the Journal of the European Academy of Dermatology and Venereology
Devaux, S., Castela, Â., Archier, E., Gallini, A., Joly, P., Miséry, L., Aractingi, S., Aubin, F., Bandyopadhyay, D., Cribier, B., Jullien, D., Maître, M., Richard, M., Jp, O., & Paul, C. (2012). Adherence to topical treatment in psoriasis: a systematic literature review. Journal of the European Academy of Dermatology and Venereology, 26(s3), 61–67. https://doi.org/10.1111/j.1468-3083.2012.04525.x
Chovatiya, R., MD PhD. (2022, July 25). Factors affecting patients adherence in topical therapies. Dermatology Times. https://www.dermatologytimes.com/view/factors-affecting-patients-adherence-in-topical-therapies
Jorge, L. L., Feres, C. C., & Teles, V. E. (2010). Topical preparations for pain relief: efficacy and patient adherence. Journal of Pain Research, 11. https://doi.org/10.2147/jpr.s9492