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 tolerability 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 formulations 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, and dapsone. the largest drug metabolizing tissue the topical formulations that effi- Follicular delivery is preferred in the body. Research has identified ciently deliver drugs. This advance- for diseases of the pilosebaceous 13 CYP2 genes expressed in human ment in skin biology has fueled the unit, such as acne, folliculitis, and skin, with most expressed in the development of novel vehicles that hair loss, but is also utilized to cre- non-vascular tissue of the have advanced dermatologic thera- ate a reservoir effect.5 Drug micro- epidermis.9 Esterases and serine propy with both new formulations of particles deposited into the follicle teases are abundant. old drugs and new drug entities. may slowly dissolve over time, cre- Biotransformation of compounds can Mechanisms of Drug ating a controlled release or reser- and often does occur in the epider- Absorption. There are three pri- voir effect. mis, presenting both challenges and mary mechanisms of topical drug In practice, drugs are absorbed opportunities to formulators. absorption: transcellular, intercellu- through combinations or perturba- Epidermal biotransformation could lar, and follicular.4 Most drugs pass tions of these pathways. For exam- render a drug such as a peptide inef- through the torturous path around ple, propylene glycol, because of its fective before it reaches its target or, corneocytes and through the lipid solvent and humectant properties, in the case of some pro-drugs, trans- bilayer to viable layers of the skin. is a common ingredient in topical form a biologically inactive molecule The next most common (and poten- formulations. At relatively high con- to an active form. Epidermal metab- tially under-recognized in the clini- centrations, propylene glycol has olism and inactivation of certain cal setting) route of delivery is via been shown to promote desquama- drugs may permit safe topical appli-

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cation of a drug that possesses sys- the dermal layer, where it can pro- treatment involves a greatly temic toxicity. duce the desired effect. increased skin and appendage sur- Gama benzene hexachloride Disease Sites and Anatomic face area that will interface with (GBH, Lindane, Morton Grove Treatment Areas. The site of the the topical delivery system. Scalp Pharmaceuticals), for example, is disease within the skin—whether it and other very hairy areas gener- largely biotransformed as it passes be the epidermis, dermis, capillar- ally require the application of through the epidermis and into ies, or the pilosebaceous unit— more drug formulation per square the dermis, therefore the risk of must be taken into account in centimeter than glabrous skin. systemic toxicity associated with designing an effective vehicle for a Additionally, the scalp is almost extensive topical application (up to drug. With the modern under- always covered by a thin layer of 30-60mL) is relatively low. By con- standing of skin biology, formula- sebum. Sebum incorporates into trast, less than 15mL of Lindane tors can target delivery of a partic- the formulation after application ingested orally is in the range of ular drug molecule by the skillful to the scalp skin, potentially alter- LD50 for humans. Topical selection of excipients and their ing the kinetics of intercellular tazarotene is another drug that is concentration, proper choice of transport. For this reason effective rapidly skin metabolized (to vehicle type, and careful attention topical formulations take into con- tazarotenic acid and other metabo- to the physical state of the active sideration the in vivo environment lites),10 accounting for its relatively ingredient (i.e., the degree of solu- from which the active ingredient low risk of systemic exposure. bility in vehicle or particle size in is delivered to the site of action Cutaneous metabolism allows the case of suspensions) and con- within the skin. for the topical application of pro- trol of the characteristics of the Drug-Specific Considerations. drugs that are transformed to secondary formulation. Similarly Specific properties of the drug to active drugs. Retinol is metabolized the anatomic location(s) of treat- be delivered guide the develop- in the dermis to retinoic acid.11 ment and the range of body sur- ment of the vehicle. Ideal vehicles However, the efficiency of bio- face area guide development of a are drug-specific; There are no transformation of retinol to retinoic vehicle that will allow the drug to vehicles that without customiza- acid is relatively low, so retinol is be applied uniformly and with rel- tion work efficiently for a wide considered safe for use as an ingre- ative ease. variety of drug molecules. The sta- dient in topical cosmetic products Clinicians know that choice of bility of the active ingredient and without retinoid safety labeling. vehicles depends on the location its bioavailability are primary con- Theoretically, pro-drugs could being treated as well as the skin siderations in creating an optimal be used in topical formulations as disease. For example, an ointment vehicle. Based on the physico- a strategy to alter the physico- is not cosmetically acceptable for chemical properties of the drug, a chemical properties of the active application to the hair-dense scalp rational strategy can be developed ingredient to improve delivery for many people. The scalp is an to create the vehicle. Key factors into the skin or to minimize toxici- interesting delivery area to consid- include: a.) degree of solubility or ty. Suppose a biologically activated er in terms of product formulation insolubility in various excipients drug is intended for delivery to because of the variability of densi- such as oils, humectants, and the dermis but is inactivated in ty and texture. Unless the topical water, b.) compatibility or incom- the epidermis. An inactive pro- formulation can be applied direct- patibility with potential excipients, drug molecule might pass through ly to the scalp skin (e.g., a foam or and c.) sensitivities to molecule the epidermis and be metabolized spray applied via a delivery tube degradation and instability. With to the biologically active drug at to pass through the hair), scalp this knowledge, the formulator

Supplement to Practical Dermatology | March 2010 | 5 Vehicles Matter

can create multiple vehicles for the become mixed with the hydrolipidic further dissolve dapsone into the drug with the goal that one will sur- film on the skin surface, creating solvent, while undissolved particles vive stability testing, assessement of what some call the “secondary for- are deposited in the follicle, creat- cosmetic and functional properties, mulation.” It is from this secondary ing a reservoir of drug slowly dis- in vitro skin penetration studies, formulation that drug is typically solved by sebum over time. At the antimicrobial preservative effective- delivered into the skin. Consider same time, sebum and other debris ness testing, and other screening difficult-to-solubilize dapsone that on the surface of the skin become criteria. The development process is has been formulated into a gel incorporated into the secondary lengthy and far from simple. (Aczone, Allergan). The marketed formulation. Secondary Formulations. formulation contains water along Of the many topical solubilizing Beyond the physicochemical consid- with a solvent called diethylene gly- agents used, propylene glycol may erations and requirements for the col monoethyl ether (also known as be the most widely used and best formulation and its physical con- DGME, Transcutol® or ethoxydigly- known. At high concentrations tainer to provide stability and uni- col). DGME solubilizes a percentage (greater than 10%) propylene glycol formity, formulators also must con- of the dapsone in the formulation; can be more irritating to the skin or sider the physical changes that the remaining undissolved dapsone provoke allergic reactions, though it occur as a formulation is applied to particles remain in suspension. is generally well-tolerated at mod- the skin. When present in a vehicle, Once the gel is applied to the erate and low concentrations. High volatile components such as water, skin, water—the highly volatile concentrations of PG may be prob- alcohol, and propellants, all eventu- component—dissipates, and dap- lematic for some individuals; The ally evaporate, thereby concentrat- sone particles become concentrated incidence of positive patch reac- ing the active drug and non-volatile in the residual non-volatile solvent tions for allergic contact dermatitis excipients. During the application DGME. As the gel is rubbed in, in those using up to 30% concen- process these residual components mechanical rubbing action helps to tration of PG is about 3.5 percent.12

Penetration Enhancers: Benefits and Challenges

n order to promote absorption humectant, solvent, and antimicro- toxic to humans.14 of drugs, vehicles often include bial. The mechanism of perme- Other penetration enhancers, penetration enhancing ingredi- ation enhancement by propylene including detergents and emulsi- Ients that temporarily disrupt glycol is multiple and varies with fiers, disrupt the barrier to encour- the skin barrier, fluidize the lipid concentration and formulation age migration of active drug through channels between corneocytes, type. Propylene glycol is common- the stratum corneum. Oleic acid can alter the partitioning of the drug ly used as an excipient in topical be a penetration enhancer in certain into skin structures, or otherwise drug formulations and is found in formulations and its mechanism is enhance delivery into skin. So- a majority of formulations of corti- thought to be through fluidizing the called penetration enhancers are costeroids. It is shown to diminish intercellular lipids of the stratum drug substance- and vehicle- barrier function,13 and often func- corneum. Isopropyl myristate (IPM) dependent and therefore are not tions as a penetration enhancer. is a unique penetration enhancer universally effective. Propylene Interestingly, despite its utility and that is thought to provide benefit by glycol is a multifunctional excipi- safety in topical formulations, fluidizing stratum corneum lipids ent in topical formulations, having propylene glycol at high doses is and partially dissolving them.15 It is

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used in clobetasol propionate 0.05% ucts, yet laboratory evidence sug- (Olux and Luxiq, Stiefel) not only spray (Clobex Spray, Galderma) to gests delivery of a similar amount provide good spreadability and encourage rapid penetration of corti- of BPO to the skin.16 This may be cosmetic elegance, but also costeroid into the treated skin. an effect of low concentration enhance delivery of corticos- Most penetration enhancing propylene glycol in the formulation teroids compared to other tradi- excipients have the potential to be that helps to solubilize the BPO tional formulations. The mecha- irritating to the skin, depending microparticles and transports them nism to enhance penetration is the upon concentration and the other into the sebum. creation of a supersaturated drug inactive ingredients in a particular The use of micrsopheres repre- solution in the propylene glycol- vehicle. sents another approach to minimiz- rich secondary formulation Only relatively recently have for- ing BPO-induced irritation. remaining on the skin after evapo- mulators focused on modulating the NeoBenz Micro (Intendis) entraps ration of the alcohol and propel- detrimental effects of penetration micronized benzoyl peroxide within lants. Supersaturation provides a enhancers by reducing or ameliorat- polymeric sponges, offering slow driving force for drug delivery ing the signs and symptoms of irrita- release of the drug over time. Slow into the skin. Despite good overall tion. Review of three modern for- release of benzoyl peroxide through tolerability with original ethanolic mulations of benzoyl peroxide microspheres is shown to reduce foams, a newer foam vehicle (BPO)—an inherently irritating drug irritation and minimize percuta- (Olux E, Stiefel) features emol- —and clindamycin demonstrate how neous absorption.17,18 lients that counter the drying vehicles may be formulated in Other attempts to minimize the effect of the ethanolic foam, efforts to reduce the irritation poten- irritancy associated with BPO thereby hydrating the skin and tial. while enhancing efficacy have providing a lubricant film to coun- Benzaclin (clindamycin, 1%, ben- focused on solubilizing the drug. A teract sensations of stinging, burn- zoyl peroxide, 5%, Sanofi-Aventis) gel and lotion formulation ing, and dryness related to contains micronized benzoyl perox- (ClenziDerm, MD, Obagi Medical ethanol.20 ide in an aqueous gel with surfac- Products) features chemically In the case of Metro 1 (metron- tant and no non-volatile solvent. micronized, solubilized BPO mole- idazole 1%, Galderma), metronida- Upon application, the micronized cules to ensure even distribution in zole is not very soluble in water BPO is deposited in the sebum-rich the vehicle. In clinical trials com- or oil, so the molecule was formu- follicle where it exerts it effects. paring solubilized BPO gel to a lated inside a dextran ring In Duac (clindamycin, 1%, ben- non-solubilized BPO/clindamycin (Betadex NF or beta cyclodextrin) zoyl peroxide, 5%, Stiefel) combination formulation, the solu- to which niacinamide was added micronized benzoyl peroxide is for- bilized gel produced a greater in order to keep 10mcg/g in solu- mulated in an aqueous gel with sur- reduction in non-inflammatory tion. Given the physicochemical factant, glycerin, a humectant to lesions at weeks 1 and 2 and an characteristics of metronidazole, minimize the desiccating effect of equivalent reduction in inflamma- optimal delivery would be predict- BPO, and the emollient dimethicone tory lesions at week 12. Solubilized ed from a solution rather than a to help moisturize the skin. BPO is shown to produce a greater suspension of the active ingredi- Acanya gel (clindamycin phos- reduction of colony forming units ent. Niacinamide is further shown phate 1.2%, benzoyl peroxide 2.5%, of P. acnes compared to combina- to improve skin hydration and Coria Laboratories) contains a 2-fold tion BPO/clindamycin.19 barrier function.21 Low concentra- lower dose of benzoyl peroxide than Ethanolic foam vehicles that tions of glycerin in the formula- the other clindamycin/BPO prod- dissolve at body temperature tion enhance percutaneus absorp-

Supplement to Practical Dermatology | March 2010 | 7 Vehicles Matter

tion and provide humectant and hydrophobic core that encap- higher concentration of metronida- effects. Betadex has a polyhydric sulates the metronidazole mole- zole than had previously been hydrophilic surface (to enhance cule. This newer formulation available, and with improved tol- solubility and moisturize the skin) enables once-daily dosing of a erability.

Topical Dosage Forms

he classification of topical The clinical significance of these dermatitis with unique skin reactivi- dosage forms has recently classifications varies; however there ty, the improper choice of vehicle been updated and codified. are many situations where the vehi- can impact therapeutic outcomes TWhile some terms commonly cle matters. Clinicians may favor leading to signs and symptoms of used to describe specific vehicles are certain dosage forms for specific cutaneous irritation, poor patient actually developed for marketing uses, and they often ascertain the compliance, and production of aller- purposes, FDA recognizes eight topi- benefits of various forms from clini- gic contact dermatitis due to a pre- cal dosage forms: Solution, cal study data, practical experience, servative. Suspension, Lotion, Paste, Gel, product package inserts, manufac- An occasional mismatch between Ointment, Cream, or “Other,” which turer's materials, and peer educa- the official designation of a product includes foams, aerosols, powders, tors. For conditions such as atopic and its practical appearance may patches, etc.22 (See Table 1.) dermatitis, psoriasis, and contact have a significant impact on patient

No Is it Pourable? Yes

Non-liquid, Non-semi-solid Liquids Semisolids “Other”: Solutions: >50% water and other <50% water and other Formulations that are Clear and homogeneous volatiles volatiles not liquid or semisolid fall Gel: Ointments: into this category, which Suspensions: Solution or colloidal More than 50% of hydro- includes aerosols, Solids dispersed in liquids dispersion stiffened with carbons, waxes or PEG powders, etc. a gelling agent and less than 20% water Lotions: and volatiles Emulsions Pastes: Contain 20-50% dispersed Table 1. Topical Dosage Forms for solids Dermatological Applications Cream: Cream: Emulsion One or both does not apply: (Based on Buhse L, et al. International Journal of Pharmaceutics; 295: 101-112.) • More than 50% of hydro- carbons, waxes or PEG • Less than 20% water and volatiles

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care. Despite its dosage form desig- 0.1% in any other dosage form A hydrogel has low residue, is non- nation, Diprolene Lotion 0.05% (lotion or gel) would need to go sticky when applied, has a high (betamethasone dipropionate, through the full NDA and review cosmetic acceptability, is free of Shering Corp.) would be categorized process in this hypothetical case. For acetone, alcohol and significant lev- as a solution under today's FDA this reason, and because choice of els of harsh solvents, and has a naming system, as the vehicle is in vehicle matters to dermatologists for very high water content. In this fact a clear hydroalcoholic solution unique and clinically important rea- sense, the term describes the con- intended for scalp treatment, and sons specific to the individual sistency and appearance of the not a fluid emulsion of oil and patient, non-dermatologists, pharma- hydrogel, as well as potential bene- water (i.e. lotion). cists, and insurance providers fits to the patient. These formula- These dosage form classifications should not substitute different tions do not sting or burn and are are particularly relevant to the dosage forms or vehicles than the associated with a lower incidence development of generic challengers one prescribed by the dermatologist. of adverse events compared to alco- of innovator formulations. To apply Gels and foams, both of which hol-based gels. Typically, a humec- for marketing approval from the will be further addressed in the sec- tant ingredient is incorporated to FDA, a generic formulation must ond installment of this series, are the provide what is called a “pillow challenge a specific existing product dosage forms that have probably wit- effect.” Whereas traditional gels dry (active drug, concentration, and nessed the greatest advancement in down very quickly and make the dosage form). For example, if the recent years. Alcohol-based gels, skin feel tight, the water-retention FDA had only approved a New Drug once considered appropriate only for properties of the humectant in a Application (NDA) for triamcinolone oily skin, have largely been replaced hydrogel impart a softness to the acetonide 0.1% cream, and no other by hydrogels and nonaqueous gels, skin. dosage form were yet available; a changing the way that clinicians Many of the gel formulations generic manufacturer could only view gels and broadening their use. marketed today are hydrogels, with challenge the branded product with The term “hydrogel” is a descrip- a few exceptions. Generic tretinoin a 0.1% cream dosage form via the tive marketing term. Although it is gel 0.025% is an alcohol gel, and inexpensive generic approval route not an official designation recog- Xolagel (Ketoconazole 2%, Stiefel) is with an Abreviated New Drug nized by the FDA, it does have a an anhydrous gel, different from a Application (ANDA). Triamcinolone technical meaning in the industry. hydrogel.

Formulating for Special Populations

n addition to the drug to be ences.24 Patient age is a potentially treatment of widespread skin dis- delivered, the site of drug significant consideration. While ease and use of topical corticos- activity, and the anatomic site the structure and function of the teroids (a more complete discus- Itargeted, formulators must also skin of a child may not differ sig- sion of factors associated with cor- consider any specific needs and nificantly from that of an adult on ticosteroids begins on p. 12). preferences of the population to a cellular basis,25 there is an Due to regulatory requirements be treated. Data and experience important physiologic difference, coupled with caution on the part of show that factors such as difficul- due to the higher ratio of skin sur- investigators, few formulations are ty of use, messiness, odors, and face to body mass in children. studied in patients under age two staining all affect patients' prefer- This is particularly relevant to the (or over age 65; See Sidebar: Age

Supplement to Practical Dermatology | March 2010 | 9 Vehicles Matter

Cosmetic Elegance

“Cosmetically elegant” is a subjective, descriptive term with a fur 5%, Galderma) however, contains masking agent that elimi- marketing rather than regulatory or classification function. For a nates the sulfurous odor. cosmetic product to be considered cosmetically elegant, it must Fragrances are the most common family of allergens to cause feel good, look good, and smell good (based on fragrance con- contact dermatitis from cosmetics. Of the roughly 2,500 fra- tent). For topical drug products, the issue of a pleasing fragrance grancing chemicals that are used in the US, about 100 are is generally not as significant; however the formulation should known or reported to be contact sensitizers. The common sensi- feel good and not have an unpleasant appearance (such as odd tizers used for patch testing are said to be found in a significant color or grainy consistency). A cosmetically elegant drug formu- percentage of cosmetic products. Yet, estimates suggest that, at lation hopefully will at least not smell bad, although some topi- most, four percent of the general population shows positive cal agents and excipients have a scent that is unpleasant to patch test to these ingredients.23 many patients. Clearly, identifying clinically relevant fragrance sensitivity can With few exceptions (such as DermaSmooth [fluocinolone be a challenge. Nonetheless, patients known to be allergic acetonide Topical Oil, 0.01%, Hill Dermaceuticals] and Renova should avoid cosmetics and topical drug products containing [tretinoin cream 0.02%]), fragrances are not added to topical sensitizing fragrances, including masking fragrances. When a drug formulations, although masking agents (typically neutraliz- patient has a known fragrance allergy, the practitioner may spec- ing fragrances) can be use—-leading to an “unscented” or “fra- ify on the prescription “Brand necessary: Patient allergic to fragrance-free” claim. Sodium sulfacetamide and sulfur combination grance.”In such cases, it is unlikely that the insurance company products for acne and rosacea usually have an unpleasant and or pharmacist will be able to identify a suitable generic product lingering odor. Rosanil wash (sodium sulfacetamide 10% and sul- to substitute.

Restrictions on Prescribing), so to adults. For this reason caution urea 10%, it offered efficacy direct evidence of safety and effica- is advised in treating the diaper equivalent to a mid-potency cy has been lacking. Nonetheless, area with topical drugs on a steroid for atopic dermatitis, but it consideration of the available data, chronic basis. Practical considera- had low tolerability.28 empirical evidence, and clinical tions, such as tolerability and ease Ethnicity. Although largely not experience typically guide the safe of application, may also influence studied, and while significant dif- use of many topical formulations in the treatment of children. Parents ferences may not be evident on the patients as young as full-term may be more likely to comply cellular level, practical considera- infants. An exception may be the with applications of formulations tions may influence management of pre-term infant where the barrier is that are spreadable, soothing, and patients based on ethnicity. not fully formed and significantly can be applied quickly, (i.e., Petroleum jelly has been shown to increased percutaneous absorption hydrocortisone butyrate 0.1% reduce transepidermal water loss and toxicity have been well-docu- lotion (water-in-oil emulsion) by 98 percent,29 making it a favor- mented.26 [Locoid Lotion, Triax able occlusive moisturizer or for- Diaper wearing can affect skin Pharmaceuticals]). mulation base. While some will not barrier function due to occlusion A parent is not likely to apply tolerate use of a petrolatum-based and potential for tissue macera- to a child's skin a formulation that ointment to some anatomic sites for tion, and in children there may be causes stinging or burning. For cosmetic reasons, some patients some enhanced drug absorption at example, when topical hydrocorti- prefer petrolatum-based products at certain anatomic sites compared sone 1% was formulated with some anatomic sites. Clinicians

10 | March 2010 | Supplement to Practical Dermatology | Vehicles Matter

Age Restrictions on Prescribing

Roughly only one-fifth of all drugs on the US market are disease at various ages within the pediatric population, the labeled for use by infants and children, and only 30 to 40 per- extent of the required animal safety studies needed to support cent of drugs have an indication for use in children under age such pediatric testing, and negotiations between the manufac- 12. Consequently, one study found, 62% of outpatient pediatric turer and FDA. Topical corticosteroids are commonly used in visits (0-17 years of age) in the US resulted in off-label prescrib- subjects younger than two, e.g., in the management of atopic ing (67% of pulmonary and dermatologic medication prescrip- dermatitis. FDA currently requires testing of corticosteroids in tions were off-label).27 Prescribing information for currently-mar- pediatric subjects if the labeled indication includes atopic der- keted topical corticosteroids may contain age limits (from a matitis. The clinical safety of some corticosteroid products have lower limit of three months up to 18 years of age and often an exteneded to children as young as two years of age, while others upper limit of 65 years of age). have data down to three months of age. The differences in These apparently arbitrary age limits are artefacts of the regu- pedictric age limitations among products is the result of the latory review and approval process. Trial designers typically labeling sought by the particular manufacturer and actual data excluded patients over age 65 because the increasing risk of supporting safety in that age cohort. Studying the HPA axis death due to cardiovascular or other natural causes inherent in effects of topical corticosteroids in very young patients builds a this older population increases the risk that a subject may die or foundation of data to support their safe use in children and also experience a serious medical event during the trial. Even if the helps to assure access to therapy for very young patients. death or event is not related to therapy, it is thereafter associated with the drug labeling. Examples of Topical Corticosteroids with Specific Age Allowances Below 2 Years Until fairly recently, FDA had not required 3 Months or older pediatric testing of drugs subject to the • Desonate Gel (desonide), 0.05%; Intendis review of an NDA. Since December 1998, • Derma-Smoothe/FS Topical Oil (fluocinolone acetonide), 0.01%; Hill Dermaceuitcals when FDA made the pediatric rule effective, • Locoid Lipocream/Lotion (hydrocortisone butyrate), 0.1%; Triax Pharmaceuticals, LLC drug manufacturers are now required to • Verdeso (desonide) Foam, 0.05%; Stiefel conduct some studies of new products in 1 Year or older the pediatric population or obtain a “pedi- • Aclovate Cream or Ointment (alclometasone dipropionate), 0.05%; GlaxoSmithKline atric waiver.”The extent of studies conducted • Cutivate Lotion (fluticasone propionate), 0.05%; PharmaDerm in the pediatric population for NDA approval • Cutivate Cream (fluticasone propionate), 0.05%; PharmaDerm these days depends on prevalence of the anecdotally have reported regional superior to vehicle in African- four male African American sub- and ethnic trends in certain vehicle American adults. Tacrolimus was jects relative to four male preferences. superior to vehicle in Caucasian Caucasian subjects.31 However, Ethnic differences in clinical adults, and there was no difference Lotte et al., using the same response to topical therapies have in response between African- methodology, reported no statisti- been documented but are poorly American and Caucasian children.30 cally significant differences in the understood. In the original trials for Wedig and Maibach reported a in vivo absorption of 14C-benzoic tacrolimus ointment 0.03% 34 percent lower in vivo absorp- acid, 14C-caffeine, and 14C-acetyl- (Protopic, Astellas) for adult atopic tion of 14C-labeled dipyrithione salicylic acid following topical dermatitis, active treatment was not following topical application to application to African American

Supplement to Practical Dermatology | March 2010 | 11 Vehicles Matter

(n=6 to 8 depending on com- female responses to certain topical- Prepubertal skin, for example, pound), Caucasian (n=9), and ly applied drugs.35,36 does not produce significant Chinese American (n=6 to 7) sub- Skin Changes throughout Life. amounts of sebum, thus the jects.32 Clearly any potential ethnic While skin structure and function biofilm is considerably different differences in skin penetration may not vary significantly based on from that of a teen. Any topical may well be formulation as well age, certain characteristics of the formulation applied to the skin as compound dependent. skin change with time. Following the mixes with and is affected by the Geographic skin differences. significant change in the skin of a natural biofilm. With age the epi- Geographic skin differences may newborn as the individual adapts dermis thins and the level of natu- also exist as a result of environment. from the watery millieau of the ral moisturizing factors decreases; For example, differences in humidi- amniotic sac to the natural environ- diminished protease levels lead to ty in the Southwestern United States ment, the next significant change in decreased rates of desquamation, compared to the North East could the skin occurs around puberty.37 potentially easing the absorption impact skin hydration, TEWL, and Additional changes occur gradually of drugs via the intercellular path- barrier function.33,34 over time, so that some variation in ways. Vehicles with moisturizing Gender. The influence of gender the skin may be seen when com- properties (i.e., those containing on topical therapy is an important pared from decade to decade of life. emollients and humectants) may consideration and a relatively new These changes can influence the be clinically desirable for deliver- area of research, with evidence delivery and activity of topical ing topical drugs in the geriatric suggesting differences in male and drugs. population.

Drug Approval and the Case of Corticosteroids

opically applied medications prior to passage of the Food, Drug, ucts based on very old active ingre- can reach the US market in and Cosmetics Act in 1938, were dients are known as “grandfathered” one of three ways: a new permitted to remain on the market. drugs or unapproved prescription Tdrug application (NDA), an Ultimately, some were submitted for products. abbreviated new drug application approval in NDAs in their existing or Since the passage of the Food, (ANDA) for generics, or by com- in new formulations. Others were Drug, and Cosmetics Act of 1938, pliance with an OTC Monograph shown to be ineffective or dangerous FDA has established strict process- as an over-the-counter (OTC or and were abandoned. In 1968, FDA es for the review and approval of non-prescription) product (see established “Drug Efficacy Study new drugs. FDA approves a specific Sidebar: OTC Monograph). Other Implementation” or DESI with the drug formulation on the basis of a topically applied products are aim of evaluating drugs that had not New Drug Application; it does not either cosmetics, which FDA does yet undergone clinical trials and approve a chemical entity or com- not approve for marketing, or review. About 160 drugs have still pound. For example, although the devices granted 510K marketing not been reviewed yet are available FDA had approved oral dapsone clearance. (See “Divining the on the market. Known as DESI more than five decades earlier, top- Details of Device Clearance,” drugs, many are still used in derma- ical dapsone gel could not come to available online at tology-coal tar, sulfur, sodium sulfac- market based on that filing. An VehiclesMatter.com). etamide, and hydroquinone, among NDA for dapsone gel 5% was sub- Drugs that had been marketed them. Sometimes these drug prod- mitted to FDA with data supporting

12 | March 2010 | Supplement to Practical Dermatology | Vehicles Matter

its strength, dosage form and new such products must demonstrate If the generic formulation indication. bioequivalence to the Reference demonstrates bioequivalence, its The costs associated with bring- Listed Drug (RLD) or innovator safety and efficacy are assumed to ing a new prescription product to through relatively inexpensive tests. be equivalent to those of the inno- market have risen significantly over Bioequivalence signifies that “the vator. The generic product must the past decade. The development rate and extent of absorption are meet most of the same chemistry costs for a new chemical entity not statistically different when and pharmacologic criteria required (NCE) as a dermatological, starting pharmaceutical equivalents are of the RLD, including establishing with formulation development administered to patients or subjects a stability-based shelf life. Costs to through NDA approval, is currently at the same molar dose under simi- bring generic topical formulations estimated to be $40-50 million or lar experimental conditions.” to market today can be from more, exclusive of the significant In order to demonstrate bioe- $500,000 to $1.5 million, unless a research costs associated with dis- quivalence to an oral RLD, a gener- clinical bioequivalence study is covery and synthesis of the com- ic oral formulation must demon- required, thus increasing the devel- pound. Because a new formulation strate equivalent bioavailability opment cost to an estimated $4-6 containing an already-approved through comparable plasma con- million. drug for a new indication, strength, centrations. For topical medica- Topical corticosteroids are or dosage form can bypass some tions, methods for demonstrating among the drugs most commonly safety studies, development costs bioequivalence are more complex prescribed by dermatologists and may be decreased to around $15-25 than for oral products and contro- represent a tremendous proportion million. Combination drug products versial. For example, plasma con- of the generic topical prescription for dermatologic use (a clin- centrations are usually very low market and therefore represent a damycin/benzoyl peroxide formula- and fail to demonstrate that a topi- suitable focus for exploring generic tion, for example) can be expected cal drug is available at the neces- drug approvals. The US topical cor- to be intermediate in cost. The sary site of activity. There are three ticosteroid market was $1.5 billion developer and/or intended marketer ways a generic topical product can in 2009 as a result of more than 35 must demonstrate that the new meet the bioavalibility require- million prescriptions, of which drug formulation is safe and effec- ment: 1.) by a bioequivalence waiv- slightly more than 90% were for tive for the intended indication in a er from FDA (commonly allowed generics. systematic step-wise manner. for solution dosage forms), 2.) by a The standard bioassay adopted by Among the many aspects that must show of “equivalence” of a corticos- FDA for demonstrating bioequiva- be addressed during the typical teroid in the vasoconstriction bioas- lence of topical corticosteorids is the four to seven year development say (described in more detail vasoconstriction assay using the period of the vehicle (from initial below), or 3.) by a demonstration Area Under the Effect Curve or design to market approval) are sta- of clinical bioequivalence for all AEUC. This bioassay is based on the bility and lack of unsafe levels of non-corticosteroid topical products findings of Stoughton and McKinzie impurities and degradation. in a three-arm study (generic prod- that corticosteroids cause skin A generic drug product seeks to uct v. RLD v. vehicle). Clinical blanching and that this surrogate match an approved drug formula- measures are variable, difficult to pharmacodynamic response is relat- tion in terms of active ingredient, control for, and may lack sensitivi- ed to potency and clinical efficacy. concentration, and dosage form. ty. Thus, such clinical bioequiva- FDA has adapted the original Besides chemistry documentation lence trials are quite large and bioassay to serve as a bioequiva- (e.g., demonstration of stability), expensive. lence assay with specific test

Supplement to Practical Dermatology | March 2010 | 13 Vehicles Matter

micro-dose, it does not provide clini- OTC Monograph cally important information, such as FDA oversight of OTC drugs differs significantly from that for prescription drugs. The minute-to-minute and hour-to-hour Office of Nonprescription Products maintains a list of more than 80 therapeutic cate- pharmacodynamics of a drug; gories of OTC drugs. The Center for Drug Evaluation and Research oversees these effects of multiple doses on the skin; agents to assure they comply with safety and labeling. The OTC Monograph outlines or the impact of the physical proper- the permitted active ingredients, dosages appropriate for OTC marketing, indications, ties of the generic vehicle on patient and label language. The OTC Monograph, in a sense, provides a recipe for OTC prod- compliance. The latter two can vary ucts, with rare specifications or restrictions on dosage form or formulations. Any manu- significantly based on the vehicle. facturer who creates a formulation under the parameters outlined and with the labeling Application time is an important indicated is able to bring that formulation to market without FDA review and approval. consideration in topical therapy, as OTC products must comply with the Monograph and Good Manufacturing Practices a drug must be given the opportu- (GMP) including documentation of stability. nity to absorb through the stratum Among OTC Monograph categories, which include antacids and aphrodisiacs, are multiple corneum. In clinical practice, some categories of relevance to dermatology: vehicles have been found to virtu- ally slide off the skin, permitting o Acne (benzoyl peroxide, salicylic acid) o Antifungals little time for drug absorption. o Antimicrobials o Antiperspirants Application site matters, as well. If o Dandruff/seborrheic dermatitis o External analgesics (poison ivy, oak, sumac) not properly formulated, a vehicle o Pediculicides o Sunscreens applied to the hands, for example, o Skin protectants (diaper rash, cold sores, insect bites, poison ivy, oak, sumac may be transferred rather quickly o Wart removers to objects or other anatomic sites or washed off. Two formulations parameters. A chromameter is used -20/+125 variability permitted for could have comparable AUECs as to measure skin blanching effect bioequivalence measures. This wide demonstrated in a laboratory, but if over an established period of time percentage variability in the deliv- one does not remain on the affect- as elicited by a topically applied ered dose of an innovator compared ed skin for an adequate time, the test formulation (T), the reference to its generic can be expected to cor- clinical implications are obvious. drug (R), and at untreated control relate with a difference in clinical Unfortunately, FDA requires no sites.38 To establish bioequivalence, efficacy. Possibly more concerning is test for clinical utility of the vehi- FDA requires that the 90% confi- the potentially significant difference cle of a generic dosage form. dence interval for the ratio of the between two generics formulations. As noted, except for the case of AUEC due to the test product and Suppose challenge product A tests in bioequivalence waivers, generic the AUEC due to the reference the -15% range, relative to the inno- manufacturers must match the product does not differ significant- vator, while challenge product B dosage form but not necessarily the ly; significance is defined as 20%. tests in the +20% range. The poten- excipients that comprise the vehi- As such: tial clinical implications for a patient cle. In order to establish equivalen- • The lowest limit for T/R = switched from A to B—such switch- cy, formulators may incorporate 80/100 or 80%. es occur frequently—are obvious. high proportions of penetration • The maximum limit for R/T = Furthermore, while bioassay data enhancers in their products to dis- 100/80 or 125%. demonstrate the effects of a topical rupt the stratum corneum and There are concerns about the corticosteroid at the conclusion of a encourage drug absorption. There clinical significance of the set period of time after a single is no requirement for assessing the

14 | March 2010 | Supplement to Practical Dermatology | important local safety parameters ClinicalTrials.gov of irritancy and skin barrier function of generic corticosteroid Nearly every clinical trial undertaken in the US today (and a majority of those conduct- creams, lotions, gels, ointments or ed around the world) is registered at ClinicalTrials.gov. An important beneficial conse- foams. quence of this public registry is that it has created a checks-and-balances system within The laboratory assays described the clinical studies community. Studies are listed during early phases and researchers are above are intended to demonstrate required to post updates (including discontinuation) and to provide access to published bioequivalence—that is, they show results. In the past, researchers could simply bury sub-optimal or unexpected results that the formulations provide simi- because few people knew that a trial was ever underway. Now, because every trial is lar bioavailability of active drug at recorded in a searchable public database, researchers today do not have that liberty. specific time points. Bioequiv- ClinicalTrials.gov is a project of the US National Institute of Health (NIH) administered alence is one component of through the National Library of Medicine (NLM) in collaboration with all NIH Institutes and “Therapeutic equivalence,” a term the FDA. The stated mission of the website is to provide “patients, family members, health which would seem to suggest that care professionals, and members of the public easy access to information on clinical trials two formulations will have equiva- for a wide range of diseases and conditions.”The database was mandated in the Food and lent efficacy in clinical use. Drug Administration Modernization Act (1997) which required the Department of Health However, according to FDA, head- and Human Services, through the NIH, to establish a registry of clinical trials for both fed- to-head clinical trials of formula- erally and privately funded trials. tions to treat active disease in The site is intended to help potential participants identify enrolling studies as well as to human subjects are not required disseminate information about trials. ClinicalTrials.gov currently contains 85,508 trials to demonstrate therapeutic equiv- sponsored by the National Institutes of Health, other federal agencies, and private indus- alance. try. Studies listed in the database are conducted in all 50 States and in 171 countries. Generic corticosteroid formulations need not repeat HPA axis test- sion, therefore claims of safety Table 2. Betamethasone ing, which is required of innovator based on comparison of HPA axis Dipropionate 0.05% or reference drugs. Although HPA results for reference formulations Potency Categorizations axis suppression is rarely a signifi- within the same potency class may Class I cant clinical concern for adults, be misleading. Yet, when modern Diprolene Cream, 0.05% HPA axis suppression in children formulations are compared to older Diprolene Ointment, 0.05% can have numerous systemic side formulations (especially consider- Class II effects, including an effect on long- ing that pre-clinicaltrials.gov some Diprolene Cream AF, 0.05% term growth, and bone formation. results were never published; See Diprosone Ointment 0.05% Increasingly, evidence suggests that Sidebar: ClinicalTrials.gov), Class III the vehicle can help to modulate enhanced safety is evident. Diprosone Cream 0.05% rate and extent of systemic absorp- Characteristics of the vehicle Class V tion associated with topical corti- can profoundly modulate the local Diprosone Lotion 0.05% costeroid delivery. and systemic safety (as previously Given advancements in mole- described) as well as the potency of cule engineering and formulation a corticosteroid. For example, Conclusion development, most modern refer- betamethasone dipropionate 0.05% The development of an appropri- ence low-potency topical corticos- is characterized in four different ate topical formulation for a given teroids are not associated with sig- potency classes, depending on the active drug is a complex, time- nificant risks of HPA axis suppres- vehicle (See Table 2). consuming, and costly process.

Supplement to Practical Dermatology | March 2010 | 15 Yet this laborious and multi-step tion of relatively few new chemi- (June 2010) will further investi- process is necessary to assure effi- cal entities in recent years, new gate specific dosage forms used in cacy, enhance compliance, and therapeutic development initia- dermatology with an emphasis on decrease the possibility of adverse tives have largely focused on vehicle development challenges events. For a field such as derma- improving vehicles to optimize and the potential for real clinical tology that has seen the introduc- treatment. Part II of this series benefits. ■

1. Proksch E, Brandner JM, Jensen JM. The skin: an indispensable barrier. Exp Dermatol. ide gel with benzoyl peroxide/clindamycin: final data from a multicenter, investigator- 2008 Dec;17(12):1063-72. blind, randomized study. J Drugs Dermatol. 2009 Sep;8(9):812-8. 2. Wiedersberg S, Naik A, Leopold CS, Guy RH. Pharmacodynamics and dermatophar- 20. Tamarkin D, Friedman D, Shemer A. Emollient foam in topical drug delivery. Expert macokinetics of betamethasone 17-valerate: assessment of topical bioavailability. Br J Opin Drug Deliv. 2006 Nov;3(6):799-807. Dermatol. 2009 Mar;160(3):676-86. 21. Crowther JM, Sieg A, Blenkiron P, Marcott C, Matts PJ, Kaczvinsky JR, Rawlings AV. 3. Harding CR. The stratum corneum: structure and function in health and disease. Measuring the effects of topical moisturizers on changes in stratum corneum thick- Dermatol Ther. 2004;17 Suppl 1:6-15. ness, water gradients and hydration in vivo. Br J Dermatol. 2008 Sep;159(3):567-77. 4. Chourasia R, Jain SK. 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Support for this educational initiative was provided by: Allergan, Inc. • Coria Laboratories (A Division of Valeant Pharmaceuticals, NA) • Ferndale Laboratories • Galderma S.A. • Intendis • Obagi Medical Products, Inc. • Ortho Dermatologics • Triax Pharmaceuticals

16 | March 2010 | Supplement to Practical Dermatology |