Review of Changes in Topical Drug Product Classification - Pharmaceutical Technology

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Review of Changes in Topical Drug Product Classification
This article summarizes the classification systems for topical liquid and semisolid dosage forms used for dermatological application and notes some differences between FDA and USP classification.

Pharmaceutical Technology
Volume 32, Issue 10, pp. 66-74

Before discussing lotions in more detail, two items of clarification are required. For the purpose of topical drug product classification, a liquid is pourable, flows and conforms to its container at room temperature, and displays Newtonian or pseudoplastic flow behavior. Although this definition is contained within the CDER Data Standards Manual, the term liquid is also a recognized dosage form and is defined as "a dosage form consisting of a pure chemical in its liquid state. This dosage form term should not be applied to solutions." It seems unlikely for a 100% active pharmaceutical ingredient (API) liquid to be developed as a topical drug product; however, it is clear that such a product would be classified as a liquid. Another CDER Data Standards Manual recognized dosage form term is emulsion, defined as "a dosage form consisting of a two-phase system comprised of at least two immiscible liquids, one of which is dispersed as droplets internal or dispersed phase) within the other liquid (external or continuous phase), generally stabilized with one or more emulsifying agents." (Note: emulsion is used as a dosage form term unless a more specific term is applicable, e.g., cream, lotion, ointment.) Thus in terms of dosage-form classification, a parenteral emulsion is more likely to be encountered than a topical emulsion because a topical emulsion would be further characterized as a cream, lotion, or ointment if the classification system by Buhse et al. is used.

As noted in the sidebar "Dosage forms to deliver pharmaceutical actives to the skin," the PDF EC considered lotion to be an outdated term that is no longer for use in the USPNational Formulary. The term topical lotion will be changed to topical emulsion, topical suspension, or topical solution. Thus, compendial taxonomy with regard to lotions is not in agreement with the Bushe et al. classification system currently being used by FDA.

The dosage form term lotion requires additional discussion. The current definition is that a lotion is "an emulsion, liquid dosage form. This dosage form is generally for external application to the skin." The current definition was adopted by the CDER Data Standards Manual on June 21, 2006. Previously, the term lotion had been used to categorize topical suspensions, solutions and emulsions intended for application to the skin. It was this ambiguity that resulted in a range of formulations, such as Diprolene (Schering Corp., Kenilworth, NJ) lotion, being classified as a lotion before 2006.

For at least the past year, it is typical for FDA to ask for a sample of product at the pre-IND meeting. Lotion dosage forms will be checked to determine whether they are pourable. This may seem like a simple test to pass, but if the product is non-Newtonian, then some shear may be required for the product to flow. For pump lotion dispensers, shear through the pump will deliver a flowing, easily spread product, or for lotion products in a bottle, a gentle squeeze of a full bottle, or shaking of a partially empty bottle induces flow. However, a product having a yield value as low as 20 D/cm2 , may not pour from an upended container with the closure removed. (The most familiar example of a pseudoplastic liquid is ketchup, once on the burger it spreads like a lotion, but pouring it from a full bottle is not always immediate.) When providing a lotion sample to FDA, be sure it readily pours from the container that you provide. Keep in mind that during evaluation by FDA, a pump or flip-top closure will probably be removed before upending the container. If the opening of the bottle is too constricted, then the product may not pour. It is best to provide product in the "to-be-marketed" packaging, rather than sending a small sample bottle for the initial FDA evaluation. If low shear is required for the product to flow, then a good shear rate versus shear stress plot should be provided.

One additional note on pseudoplastic liquids, it is almost always desirable for liquid formulations to be pseudoplastic. Shear thinning improves mixing during processing and thus provides a higher quality, increased homogeneity product. If anything is suspended in the liquid (e.g., suspended API or the internal phase of an emulsion), then having a high yield value is the primary mechanism for preventing separation of the product. Although pseudoplastic liquids may require care during pumping and transporting to ensure that nothing "shakes-out," in general the formulation advantages we associate with increased viscosity are really the benefits of pseudoplastic rheology. Thus, formulation selection should focus on delivery of the active and quality of the product and not a nonscientific concern about the product not pouring out of the bottle while the sample is at FDA.


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