Topical Dermatological Drug Development
When developing topical drug products, particularly for dermatological applications, much consideration must be given to the vehicle used in the formulation, as the vehicle can be an active contributor to the efficacy of the drug used to treat a variety of conditions.
The majority of topical formulations are applied to the skin, and topical formulations are developed for optimal permeation of the drug into skin layers. Topical formulations, at their most basic level, consist of an active pharmaceutical ingredient (API) and a vehicle that is combined with the active ingredient to aid in the delivery of the API. Vehicles, at their highest level, can be classified into three primary categories: powders, oils, and liquids. The way in which medicine is delivered is directly related to the properties of the vehicle; for example, aqueous or alcohol-based vehicles can help to promote the drying of weeping or wet skin as the liquid vehicle used in the formulation evaporates. Vehicles serve several important purposes when it comes to dermatological topical formulations, including maintaining stability of the drug and releasing the active ingredient into the skin, allowing the API to effectively achieve dermal, or percutaneous, absorption. In summary, the vehicle used in a topical formulation has a direct impact on the permeability, and therefore the efficacy, of the drug.
Core considerations for determining the optimal vehicle for topical drug delivery systems
Several considerations will aid in the choice of the vehicle used in a dermatological topical drug product, including the nature of the skin disease, treatment site, efficacy, and patient preference. An optimal vehicle for a topical drug product will enable the efficient and even distribution of the drug substance on the skin. Furthermore, the vehicle needs to facilitate the effective release of the drug substance into the skin, enabling percutaneous absorption of the active ingredient, and ultimately, delivery of the drug to the target site. In addition to meeting cosmetic and aesthetic needs of the patient, the vehicle must achieve a sustained therapeutic level of the drug in tissue long enough for the desired pharmacological outcome to be experienced by the patient.
While the importance of the vehicle has been discussed thus far, it is important to note that the physical properties of the API also have a significant impact on the rate and extent of absorption, and ultimately, the therapeutic effect. To that end, the selection and development of ideal vehicles for topical formulations is informed and driven by the active ingredient. As there are no “one-size-fits-all” vehicles that work for a wide range of drug substances - all topical drug delivery vehicles require optimization and customization. During drug development, both the bioavailability and stability of the active ingredient are of utmost importance as the vehicle is being created and optimized. Other considerations during vehicle development include the solubility of the API in a variety of excipients, the compatibility of the drug substance with excipients, and physicochemical properties that may lead to degradation and instability of the formulation. Particular attention should be paid to the grade of excipients used within the vehicle. Unexpected outcomes, including degradation and instability, can result from differences in molecular weight and other variations seen in differing grades of excipients. Furthermore, the compatibility of the active ingredient, excipients and solvents with container-closure and packaging systems must also be evaluated to ensure the final packaged product meets all extractable and leachable requirements.
Common topical vehicles for dermatological applications
Different formulations are better suited to certain sites of application for topical drug products and aligning the topical vehicle/formulation with ease of use and application area can improve patient adherence to a treatment regimen. Figure 1 provides a decision tree for determining the type of vehicle used in a topical product, and although not exhaustive, an overview of several common topical vehicle formulations is provided below.
Solution – Seeing that topical solutions are very thin and light, they are easily spreadable and can be applied to various treatment sites. Topical solutions are often used in the treatment of scalp conditions, which is not true of all topical vehicles. However, application can be messy, and solutions often do not have properties that aid in skin hydration.
Suspension – Topical suspensions are generally easy to apply, and many produce a cooling and soothing effect when applied to the skin. Typically, topical suspensions require patients to shake the product prior to application and use, which can result in a barrier to adherence to treatment for some patients.
Lotion – Although lotions are less hydrating than ointments or creams, the ease of use and application, even to hair-bearing areas, in addition to the drying effect they provide through evaporation after application, make them ideal for the treatment of moist or weeping skin lesions. It is important to note that lotions are the least potent topical vehicle, as they are only marginally occlusive.
Ointment – Ointments increase skin hydration and temperature, and their more occlusive nature facilitates better penetration of the active ingredient through the skin. Dry skin lesions and areas of the body with thicker skin are ideal application sites. However, ointments are less cosmetically favorable for many patients due to their greasy texture and appearance.
Cream – Easily spreadable and less greasy than ointments, creams can be applied to multiple treatment sites on the body and are popular amongst both patients and clinicians. Although creams are less hydrating than ointments, their drying effect lends itself to the treatment of wet or damp skin lesions.
Gel – Easy to apply, gels are cosmetically pleasing due to the fact that they generally do not have a greasy texture and form a thin film once dry. Typically, gel vehicles provide a cooling sensation and are easily applied to and washed off the skin. However, gels are neither occlusive nor emolliating, and do not hydrate the skin.
Figure 1. Decision tree for vehicle determination in a topical dermatological product formulation
Optimize topical drug products with the right CDMO partner
A strategic partnership with the right contract development and manufacturing organization (CDMO) can be the difference between a highly effective topical drug product with an optimized vehicle and a topical drug product that just meets the target expectations. Element’s consultative formulation scientists have years of experience developing efficacious, safe, and optimized topical drugs. To learn more about Element’s topical product development and clinical-stage manufacturing services, or to explore a partnership with Element, contact us today.
Alex Garner, Director of Formulation and Clinical Trial Manufacturing, Element Materials Technology
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