Soft drugs: design principles and topical applications.

The rational design of soft drugs has emerged as a powerful strategy to enhance drug safety, without compromising efficacy. Unlike conventional active pharmaceutical ingredients, soft drugs are deliberately designed to undergo predictable and rapid metabolic inactivation after exerting their therapeutic effect. Systemic soft drugs are particularly valuable in anaesthesiology, where rapid offset of action is desirable. Regarding topical administration, the soft drug approach enables potent local activity while minimizing systemic exposure and toxicity. However, despite these advantages and the market approval of several soft drugs, especially in dermatological, inhaled and gut-restricted therapies, the concept remains underutilized and often misunderstood, frequently being conflated with prodrugs. This Review revisits the concept of soft drugs from a modern perspective, clarifies its distinction from related approaches, highlights recent clinical successes in topical delivery, and provides practical insights into the application of soft drug design in drug discovery.