There has been increased interest in the development of topical drug products as a way to deliver drugs locally, rather than systemically and for diseases that occur in the skin, mucosal surfaces, the eye, and/or wounds of these surfaces. There are reduced side effects and toxicity to other organs compared to systemic delivery. Topical drug products are typically formulated to enable the application of one or more drugs to one of four areas: the skin, mucosal surfaces, the eye, and wounds.
In this first part of a two-part blog article, we address the specific requirements of products formulated for dermal (skin) and mucosal application. Whilst the same principles of formulation science also apply to products for ophthalmic and wound care there are additional requirements (sterility, endotoxins) and will not be discussed in these blog articles.
We will first look at dermally applied products first. The outermost layer of the skin is a thin, hydrophobic layer of dead cells called the stratum corneum. It has a protective function and acts as a very effective barrier to moisture flux. As this is the surface upon which dermatological products are applied it is best that the product (or at least that part of the product containing the drug) is lipophilic.
In contrast, the surfaces of mucosal membranes are covered with a layer of hydrophilic glycoproteins and mucins (along with other compounds such as antimicrobial enzymes and immunoglobulins). Because of this, formulations intended for application to mucosal membranes need to be hydrophilic.
Products applied to mucosal membranes are typically intended to address issues within the mucus such as infections or in the very outermost cell layers such as inflammation. The high rate of mucus production by the mucous membranes generally precludes deep penetration of the drug into the membranes.
Products applied to the skin may be intended for a purely surface effect. This includes the hair follicles (e.g., for alopecia) and sebaceous glands (for acne). In this case, no penetration of the drug through the stratum corneum is required (or desired).
For other dermatological indications penetration through the stratum corneum will be required when the drug needs to act in the epidermis (e.g., psoriasis), the basal cell layer (e.g., basal cell carcinoma) or the dermis.
Drug penetration beyond the dermis, into the subcutaneous layer and beyond is rarely required. Applying drugs topically for systemic administration (e.g., nicotine and nitroglycerine) is best achieved through patch technology.
From a regulatory viewpoint, there are two types of topical drug products: those available only upon prescription (Rx) and those available “over-the-counter” (OTC) in pharmacies and other stores.
OTC products come in two regulatory “flavors”:
Those that conform to one of the published monographs that describe, in detail the acceptable active ingredient(s) and the amounts permitted, (frequently) the acceptable inactive ingredients and the labeling requirements. Such products do not require FDA review and approval prior to marketing. 21 CFR part 330 provides a detailed overview of this class of drug products.
For topical administration there are five applicable monographs:
- 21 CFR part 333 – topical antimicrobial products
- 21 CFR part 344 – topical otic products
- 21 CFR part 348 – topical analgesic products
- 21 CFR part 349 – topical ophthalmic products (note these are sterile products)
- 21 CFR part 358 – miscellaneous external products
For those drug products that do not conform to one of the monographs, the process for FDA approval is the same as that for an Rx drug- an NDA, ANDA or 505(b)(2) application (whichever is appropriate) is filed.
In part two of this blog post, we will discuss the various types of topical products (ointments, creams, gels, sprays, and lotions), detailing their characteristics both in terms of formulation and use.
Guest post by Dr. David Barnes
Dr. David Barnes is the founder, chief executive officer, and chief scientific officer of Velesco Pharmaceutical Services. Dave’s expertise is in drug formulation and drug product development.