Formulation Development, Testing, and Approval Part I of 2 Leon H. Kircik, MD, Joseph B. Bikowski, MD David E. Cohen, MPH, MD Zoe Diana Draelos, MD Adelaide Hebert, MD March 2010 Vehicles Matter elcome to Vehicles Matter, Part I, the first in a two-part series that Table of Contents Wexplores the important role of the vehicle on the efficacy, safety, and tol- erability of a drug formulation. Starting with the process of formulation plan- Topical Drug Delivery . 3 ning through the FDA approval process, this first edition of Vehicles Matter Penetration Enhancers: elucidates the critical considerations that go into designing a new topical Benefits and Challenges. 6 therapy. In Part II (June 2010), we’ll take a closer look at specific drug formula- tions in order to better understand the unique ways that these various prod- Topical Dosage Forms . 8 ucts address the challenges of formulation to ensure tolerability and efficacy. Formulating for Special Populations . 9 The insights you’ll find in this supplement represent the combined knowl- Drug Approval and the edge of a panel of specialists, with expertise in pediatrics, allergic contact der- Case of Corticosteroids . 12 matitis, clinical practice, and research. This seven-member panel convened for a lively and informative dialogue in November 2009. Support for this educational initiative was provided by: I am confident that this innovative and exciting supplement series to Practical Dermatology will help you make more informed therapeutic deci- Allergan, Inc. sions and more effectively communicate those decisions with your patients, Coria Laboratories colleagues, and others involved in patient care. Be sure to visit (A Division of Valeant Pharmaceuticals, NA) VehiclesMatter.com on a regular basis for additional information, a glossary of Ferndale Laboratories important terms, updates on new formulations, and patient education Galderma S.A. resources. I hope you find this content as informative as we did, and I thank our pan- Intendis elists for participating in this important initiative. Obagi Medical Products, Inc. — Leon H. Kircik, MD Ortho Dermatologics Program Chair Triax Pharmaceuticals Roundtable Panelists Leon H. Kircik, MD, Chair Joseph B. Bikowski, MD David E. Cohen, MPH, MD Clinical Associate Professor of Clinical Assistant Professor Vice Chairman for Clinical Affairs Dermatology of Dermatology Director of Allergic, Occupational, and Mount Sinai Medical Center Ohio State University Environmental Dermatology Indiana University School of Medicine Bikowski Skin Care Center New York University School of Medicine Physicians Skin Care, PLLC Sewickley, PA Department of Dermatology DermResearch, PLLC New York, NY Louisville, KY Zoe Diana Draelos, MD Adelaide Hebert, MD Dennis P. West, PhD, FCCP, CIP Consulting Professor Professor of Dermatology and Pediatrics Vincent W. Foglia Family Research Department of Dermatology Director, Division of Pulmonary, Critical Care Professor of Dermatology Duke University School of Medicine and Allergy-Immunology Medicine Professor in Dermatology, Pediatrics Durham, NC University of Texas-Houston Medical School Feinberg School of Medicine Houston, TX Northwestern University Chicago, IL The following conflict disclosures have been provided by panelists: Dr. Bikowski has served on the speaker's bureau or advisory board or is a shareholder or consultant to Allergan, Coria, Galderma, GlaxoSmithKline, Intendis, Medicis, Promius, Quinnova, Ranbaxy, Stiefel, and Warner-Chilcott. • Dr. Draelos has served as a researcher for Allergan, Inc., Coria Laboratories, Galderma, Intendis, Ortho Dermatologics, and Triax Pharmaceuticals. • Dr. Kircik has served as a researcher, consultant, of speaker for Allergan, Coria, Dermik, Ferndale, Galderma, GlaxoSmithKline, Intendis, Medicis, Obagi Medical Products, Inc., OrthoDermatologics, Stiefel, and Triax. • Dr. West has relationships with Astellas, Novartis, Leo, Genentech, Celgene, Ortho, Stiefel, GlaxoSmithKline, Sage Products. 2 | March 2010 | Supplement to Practical Dermatology | Vehicles Matter VEHICLES MATTER Part I: Formulation Development, Testing, and Approval very time that a dermatologist offers the best efficacy, among other process allows the prescriber to prescribes a topical therapy, considerations. Although clinicians better make treatment selections. that decision represents the make therapeutic selections based From the initial considerations of Eculmination of several impor- on their unique knowledge and the product formulator to the tant considerations. Often the clini- extensive clinical experience, these scrutiny provided by the Food and cian knows which active agent is decisions are frequently disregarded Drug Administration (FDA), signif- most appropriate for the skin dis- and therapeutic substitution occurs icant resources of time, money, ease being treated, but he or she at the pharmacy. and intellect go into the develop- must determine: which dosage form The practitioner should be ment of a topical drug formula- is most appropriate for the anatomic familiar with the drug develop- tion. The following is an overview site of treatment, which formulation ment process that brings formula- of the topical drug development will provide the least discomfort to tions to the market. Expanded and FDA’s approval process with the patient with the lowest risk of knowledge of the formulation emphasis on those aspects that adverse events, and which product development and drug approval have clinical relevance. Topical Drug Delivery he epidermal barrier func- cle development by exploring and the anatomic site to be treated. tions to prevent entry of answering a series of key questions 6. Be cosmetically acceptable to the chemicals and noxious mate- about the formulation to be devel- patent. T rials,1 thus the most signifi- oped. Six primary considerations Due to the efficiency of the epider- cant challenge in topical drug deliv- guide the development of a vehicle. mal barrier, the amount of topical ery is designing an appropriate The vehicle must: drug that gets through the stratum vehicle. For this reason formulators 1. Efficiently deposit the drug on corneum is generally low. Rate and must understand the structure and the skin with even distribution. extent of absorption vary depending function of the stratum corneum in 2. Release the drug so it can on characteristics of the vehicle but order to optimize delivery of drugs migrate freely to the site of is also influenced by the active agent to the intended site of activity with- action. itself. Topical corticosteroids are rep- in the skin. Formulation develop- 3. Deliver the drug to the target site. resentative of many commercially ment projects begin with the identi- 4. Sustain a therapeutic drug level available topical drug products fication of the active ingredient to in the target tissue for a suffi- regarding bioavailability of lipid-like be used to provide a desired effect. cient duration to provide a phar- drugs through skin. These agents A target product profile is devel- macologic effect. result in systemic absorption oped, establishing the goals of vehi- 5. Be appropriately formulated for through intact, non-inflamed skin of Supplement to Practical Dermatology | March 2010 | 3 Vehicles Matter tion,6,7 thus widening the cellular Transdermal Drug Delivery pathways through which topically applied drugs may pass. For topical dermatologic formulations, the therapeutic goal is typically that of tran- Hydration of the stratum sition of the epidermis so that the active agent can act at the junction or in the der- corneum is an important tool for mis. Alternatively, the active agent can enter the follicle where it directly targets follic- modifying drug delivery. As epider- ular tissues or microorganisms (e.g. P. acnes) or, in some cases or to some extent, pen- mal cells swell, the aqueous/lipid etrates the follicular epithelium to reach the dermis. The objective is to concentrate ratios within the skin are altered local delivery and to minimize systemic exposure. and, as a secondary effect, those Some systemic medications are delivered transdermally through patches. The cells no longer resist mechanical mechanisms of delivery differ significantly from those employed for drugs delivered sheering and stress forces. to targeted skin tissues. The high concentration of the active drug in a transdermal Hydration also helps maintain nor- patch, coupled with the effects of occlusion using adhesive materials, create the mal desquamation, as the serine physical/chemical conditions that drive the active drug through the epidermis and proteases that instigate dissolution the dermis into the blood stream, at a controlled rate. Given the physical and chemi- of the desmosomes require water.8 cal characteristics that allow for transdermal delivery, only certain molecules are can- In certain disease states, such as didates for such delivery. psoriasis, water can encourage desquamation of the corneocytes and thus enhance penetration of a typically less than 5% of applied the pilosebaceous route. Follicular drug through thick, scaly plaques. drug.2 delivery is typical of several com- Drug Metabolism. The epidermis Knowledge of skin barrier func- monly used drugs that are present is not simply a passive membrane tion has expanded in the last two in vehicles as fine particulate sus- that either blocks or permits entry of decades,3 elucidating both the man- pensions: benzoyl peroxide, azeleic a drug. The skin, rich in enzymes, is ner in which drugs penetrate and acid,