drug approval strategies

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Formulation Development, Testing, and Approval 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



V e h i c l e s M a t t e r

Welcome to Vehicles Matter, Part I , the first in a two-part series that

explores the important role of the vehicle on the efficacy, safety, and tol-

erability of a drug formulation. Starting with the process of formulation plan-

ning through the FDA approval process, this first edition of Vehicles Matter

elucidates the critical considerations that go into designing a new topical

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-

ucts address the challenges of formulation to ensure tolerability and efficacy.

The insights you’ll find in this supplement represent the combined knowl-

edge of a panel of specialists, with expertise in pediatrics, allergic contact der-

matitis, clinical practice, and research. This seven-member panel convened fora lively and informative dialogue in November 2009.

I am confident that this innovative and exciting supplement series to

Practical Dermatology will help you make more informed therapeutic deci-

sions and more effectively communicate those decisions with your patients,

colleagues, and others involved in patient care. Be sure to visit

VehiclesMatter.com on a regular basis for additional information, a glossary of

important terms, updates on new formulations, and patient education

resources.

I hope you find this content as informative as we did, and I thank our pan-

elists for participating in this important initiative.

— Leon H. Kircik, MD

Program Chair

Table of Con t ent s

2 | March 2010 | Supplement to Practical Dermatology |

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

Topical Drug Delivery . . . . . . . . . . . . . . . . . . . 3

Penetration Enhancers:Benefits and Challenges . . . . . . . . . . . . . . . . . 6

Topical Dosage Forms. . . . . . . . . . . . . . . . . . . 8

Formulating for Special Populations . . . . . 9

Drug Approval and theCase of Corticosteroids . . . . . . . . . . . . . . . 12

Rou nd t able Panel ist sLeon H. Kircik, MD, ChairClinical Associate Professor of DermatologyMount Sinai Medical CenterIndiana University School of MedicinePhysicians Skin Care, PLLCDermResearch, PLLCLouisville, KY

Joseph B. Bikowski, MDClinical Assistant Professorof DermatologyOhio State UniversityBikowski Skin Care CenterSewickley, PA

David E. Cohen, MPH, MDVice Chairman for Clinical AffairsDirector of Allergic, Occupational, andEnvironmental DermatologyNew York University School of MedicineDepartment of DermatologyNew York, NY

Zoe Diana Draelos, MDConsulting ProfessorDepartment of DermatologyDuke University School of Medicine

Durham, NC

Adelaide Hebert, MDProfessor of Dermatology and PediatricsDirector, Division of Pulmonary, Critical Careand Allergy-Immunology Medicine

University of Texas-Houston Medical SchoolHouston, TX

Dennis P. West, PhD, FCCP, CIPVincent W. Foglia Family ResearchProfessor of DermatologyProfessor in Dermatology, Pediatrics

Feinberg School of MedicineNorthwestern UniversityChicago, 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., CoriaLaboratories, 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.



Every time that a dermatologist

prescribes a topical therapy,

that decision represents theculmination of several impor-

tant considerations. Often the clini-

cian knows which active agent is

most appropriate for the skin dis-

ease being treated, but he or she

must determine: which dosage form

is most appropriate for the anatomic

site of treatment, which formulation

will provide the least discomfort to

the patient with the lowest risk of

adverse events, and which product

offers the best efficacy, among other

considerations. Although clinicians

make therapeutic selections basedon their unique knowledge and

extensive clinical experience, these

decisions are frequently disregarded

and therapeutic substitution occurs

at the pharmacy.

The practitioner should be

familiar with the drug develop-

ment process that brings formula-

tions to the market. Expanded

knowledge of the formulation

development and drug approval

process allows the prescriber to

better make treatment selections.

From the initial considerations of the product formulator to the

scrutiny provided by the Food and

Drug Administration (FDA), signif-

icant resources of time, money,

and intellect go into the develop-

ment of a topical drug formula-

tion. The following is an overview

of the topical drug development

and FDA’s approval process with

emphasis on those aspects that

have clinical relevance.

Supplement to Practical Dermatology | March 2010 | 3

VEHICLES MATTERPart I: Formulation Development, Testing, and Approval


T he epidermal barrier func-

tions to prevent entry of

chemicals and noxious mate-

rials,1 thus the most signifi-

cant challenge in topical drug deliv-

ery is designing an appropriate

vehicle. For this reason formulators

must understand the structure and

function of the stratum corneum in

order to optimize delivery of drugsto the intended site of activity with-

in the skin. Formulation develop-

ment projects begin with the identi-

fication of the active ingredient to

be used to provide a desired effect.

A target product profile is devel-

oped, establishing the goals of vehi-

cle development by exploring and

answering a series of key questions

about the formulation to be devel-

oped. Six primary considerations

guide the development of a vehicle.

The vehicle must:

1. Efficiently deposit the drug on

the skin with even distribution.

2. Release the drug so it can

migrate freely to the site of action.

3. Deliver the drug to the target site.

4. Sustain a therapeutic drug level

in the target tissue for a suffi-

cient duration to provide a phar-

macologic effect.

5. Be appropriately formulated for

the anatomic site to be treated.

6. Be cosmetically acceptable to the

patent.

Due to the efficiency of the epider-

mal barrier, the amount of topical

drug that gets through the stratum

corneum is generally low. Rate and

extent of absorption vary depending

on characteristics of the vehicle but

is also influenced by the active agentitself. Topical corticosteroids are rep-

resentative of many commercially

available topical drug products

regarding bioavailability of lipid-like

drugs through skin. These agents

result in systemic absorption

through intact, non-inflamed skin of

Topical Drug Delivery



typically less than 5% of applied

drug.2

Knowledge of skin barrier func-

tion has expanded in the last two

decades,3 elucidating both the man-

ner in which drugs penetrate and

the topical formulations that effi-

ciently deliver drugs. This advance-

ment in skin biology has fueled the

development of novel vehicles that

have advanced dermatologic thera-

py with both new formulations of

old drugs and new drug entities.

M echanism s of D rug

Absorption. There are three pri-

mary mechanisms of topical drug

absorption: transcellular, intercellu-lar, and follicular.4 Most drugs pass

through the torturous path around

corneocytes and through the lipid

bilayer to viable layers of the skin.

The next most common (and poten-

tially under-recognized in the clini-

cal setting) route of delivery is via

the pilosebaceous route. Follicular

delivery is typical of several com-

monly used drugs that are present

in vehicles as fine particulate sus-

pensions: benzoyl peroxide, azeleic

acid, and dapsone.

Follicular delivery is preferred

for diseases of the pilosebaceous

unit, such as acne, folliculitis, and

hair loss, but is also utilized to cre-

ate a reservoir effect.5 Drug micro-

particles deposited into the follicle

may slowly dissolve over time, cre-

ating a controlled release or reser-

voir effect.

In practice, drugs are absorbed

through combinations or perturba-tions of these pathways. For exam-

ple, propylene glycol, because of its

solvent and humectant properties,

is a common ingredient in topical

formulations. At relatively high con-

centrations, propylene glycol has

been shown to promote desquama-

tion,6,7 thus widening the cellular

pathways through which topically

applied drugs may pass.

Hydration of the stratum

corneum is an important tool for

modifying drug delivery. As epider-

mal cells swell, the aqueous/lipid

ratios within the skin are altered

and, as a secondary effect, those

cells no longer resist mechanical

sheering and stress forces.Hydration also helps maintain nor-

mal desquamation, as the serine

proteases that instigate dissolution

of the desmosomes require water.8

In certain disease states, such as

psoriasis, water can encourage

desquamation of the corneocytes

and thus enhance penetration of a

drug through thick, scaly plaques.

D rug M etabol ism . The epidermis

is not simply a passive membrane

that either blocks or permits entry of

a drug. The skin, rich in enzymes, is

the largest drug metabolizing tissue

in the body. Research has identified

13 CYP2 genes expressed in human

skin, with most expressed in the

non-vascular tissue of the

epidermis.9 Esterases and serine pro-

teases are abundant.

Biotransformation of compounds can

and often does occur in the epider-

mis, presenting both challenges and

opportunities to formulators.

Epidermal biotransformation couldrender a drug such as a peptide inef-

fective before it reaches its target or,

in the case of some pro-drugs, trans-

form a biologically inactive molecule

to an active form. Epidermal metab-

olism and inactivation of certain

drugs may permit safe topical appli-



For topical dermatologic formulations, the therapeutic goal is typically that of tran-

sition of the epidermis so that the active agent can act at the junction or in the der-

mis. Alternatively, the active agent can enter the follicle where it directly targets follic-

ular tissues or microorganisms (e.g. P. acnes) or, in some cases or to some extent, pen-

etrates the follicular epithelium to reach the dermis. The objective is to concentrate

local delivery and to minimize systemic exposure.

Some systemic medications are delivered transdermally through patches. The

mechanisms of delivery differ significantly from those employed for drugs deliveredto targeted skin tissues. The high concentration of the active drug in a transdermal

patch, coupled with the effects of occlusion using adhesive materials, create the

physical/chemical conditions that drive the active drug through the epidermis and

the dermis into the blood stream, at a controlled rate. Given the physical and chemi-

cal characteristics that allow for transdermal delivery, only certain molecules are can-

didates for such delivery.

Transderm al Drug Del ivery




cation of a drug that possesses sys-

temic toxicity.

Gama benzene hexachloride

(GBH, Lindane, Morton Grove

Pharmaceuticals), for example, is

largely biotransformed as it passes

through the epidermis and into

the dermis, therefore the risk of

systemic toxicity associated with

extensive topical application (up to

30-60mL) is relatively low. By con-trast, less than 15mL of Lindane

ingested orally is in the range of

LD50 for humans. Topical

tazarotene is another drug that is

rapidly skin metabolized (to

tazarotenic acid and other metabo-

lites),10 accounting for its relatively

low risk of systemic exposure.

Cutaneous metabolism allows

for the topical application of pro-

drugs that are transformed to

active drugs. Retinol is metabolized

in the dermis to retinoic acid.11

However, the efficiency of bio-

transformation of retinol to retinoic

acid is relatively low, so retinol is

considered safe for use as an ingre-

dient in topical cosmetic products

without retinoid safety labeling.

Theoretically, pro-drugs could

be used in topical formulations as

a strategy to alter the physico-

chemical properties of the active

ingredient to improve delivery

into the skin or to minimize toxici-ty. Suppose a biologically activated

drug is intended for delivery to

the dermis but is inactivated in

the epidermis. An inactive pro-

drug molecule might pass through

the epidermis and be metabolized

to the biologically active drug at

the dermal layer, where it can pro-

duce the desired effect.

D isease Sites and A nat om ic

Treatment Areas. The site of the

disease within the skin—whether it

be the epidermis, dermis, capillar-

ies, or the pilosebaceous unit—

must be taken into account in

designing an effective vehicle for a

drug. With the modern under-

standing of skin biology, formula-tors can target delivery of a partic-

ular drug molecule by the skillful

selection of excipients and their

concentration, proper choice of

vehicle type, and careful attention

to the physical state of the active

ingredient (i.e., the degree of solu-

bility in vehicle or particle size in

the case of suspensions) and con-

trol of the characteristics of the

secondary formulation. Similarly

the anatomic location(s) of treat-

ment and the range of body sur-

face area guide development of a

vehicle that will allow the drug to

be applied uniformly and with rel-

ative ease.

Clinicians know that choice of

vehicles depends on the location

being treated as well as the skin

disease. For example, an ointment

is not cosmetically acceptable for

application to the hair-dense scalp

for many people. The scalp is an

interesting delivery area to consid-er in terms of product formulation

because of the variability of densi-

ty and texture. Unless the topical

formulation can be applied direct-

ly to the scalp skin (e.g., a foam or

spray applied via a delivery tube

to pass through the hair), scalp

treatment involves a greatly

increased skin and appendage sur-

face area that will interface with

the topical delivery system. Scalp

and other very hairy areas gener-

ally require the application of

more drug formulation per square

centimeter than glabrous skin.

Additionally, the scalp is almost

always covered by a thin layer of

sebum. Sebum incorporates intothe formulation after application

to the scalp skin, potentially alter-

ing the kinetics of intercellular

transport. For this reason effective

topical formulations take into con-

sideration the in vivo environment

from which the active ingredient

is delivered to the site of action

within the skin.

D rug-Specific Considerat ions.

Specific properties of the drug to

be delivered guide the develop-

ment of the vehicle. Ideal vehicles

are drug-specific; There are no

vehicles that without customiza-

tion work efficiently for a wide

variety of drug molecules. The sta-

bility of the active ingredient and

its bioavailability are primary con-

siderations in creating an optimal

vehicle. Based on the physico-

chemical properties of the drug, a

rational strategy can be developed

to create the vehicle. Key factors

include: a.) degree of solubility orinsolubility in various excipients

such as oils, humectants, and

water, b.) compatibility or incom-

patibility with potential excipients,

and c.) sensitivities to molecule

degradation and instability. With

this knowledge, the formulator





can create multiple vehicles for the

drug with the goal that one will sur-

vive stability testing, assessement of

cosmetic and functional properties,

in vitro skin penetration studies,

antimicrobial preservative effective-

ness testing, and other screening

criteria. The development process is

lengthy and far from simple.

Secondar y Form ul ation s.

Beyond the physicochemical consid-erations and requirements for the

formulation and its physical con-

tainer to provide stability and uni-

formity, formulators also must con-

sider the physical changes that

occur as a formulation is applied to

the skin. When present in a vehicle,

volatile components such as water,

alcohol, and propellants, all eventu-

ally evaporate, thereby concentrat-

ing the active drug and non-volatile

excipients. During the application

process these residual components

become mixed with the hydrolipidic

film on the skin surface, creating

what some call the “secondary for-

mulation.” It is from this secondary

formulation that drug is typically

delivered into the skin. Consider

difficult-to-solubilize dapsone that

has been formulated into a gel

(Aczone, Allergan). The marketed

formulation contains water along

with a solvent called diethylene gly-col monoethyl ether (also known as

DGME, Transcutol®or ethoxydigly-

col). DGME solubilizes a percentage

of the dapsone in the formulation;

the remaining undissolved dapsone

particles remain in suspension.

Once the gel is applied to the

skin, water—the highly volatile

component—dissipates, and dap-

sone particles become concentrated

in the residual non-volatile solvent

DGME. As the gel is rubbed in,

mechanical rubbing action helps to

further dissolve dapsone into the

solvent, while undissolved particles

are deposited in the follicle, creat-

ing a reservoir of drug slowly dis-

solved by sebum over time. At the

same time, sebum and other debris

on the surface of the skin become

incorporated into the secondary

formulation.

Of the many topical solubilizing

agents used, propylene glycol maybe the most widely used and best

known. At high concentrations

(greater than 10%) propylene glycol

can be more irritating to the skin or

provoke allergic reactions, though it

is generally well-tolerated at mod-

erate and low concentrations. High

concentrations of PG may be prob-

lematic for some individuals; The

incidence of positive patch reac-

tions for allergic contact dermatitis

in those using up to 30% concen-

tration of PG is about 3.5 percent.12

In order to promote absorption

of drugs, vehicles often include

penetration enhancing ingredi-

ents that temporarily disrupt

the skin barrier, fluidize the lipid

channels between corneocytes,

alter the partitioning of the drug

into skin structures, or otherwiseenhance delivery into skin. So-

called penetration enhancers are

drug substance- and vehicle-

dependent and therefore are not

universally effective. Propylene

glycol is a multifunctional excipi-

ent in topical formulations, having

humectant, solvent, and antimicro-

bial. The mechanism of perme-

ation enhancement by propylene

glycol is multiple and varies with

concentration and formulation

type. Propylene glycol is common-

ly used as an excipient in topical

drug formulations and is found ina majority of formulations of corti-

costeroids. It is shown to diminish

barrier function,13 and often func-

tions as a penetration enhancer.

Interestingly, despite its utility and

safety in topical formulations,

propylene glycol at high doses is

toxic to humans.14

Other penetration enhancers,

including detergents and emulsi-

fiers, disrupt the barrier to encour-

age migration of active drug through

the stratum corneum. Oleic acid can

be a penetration enhancer in certain

formulations and its mechanism isthought to be through fluidizing the

intercellular lipids of the stratum

corneum. Isopropyl myristate (IPM)

is a unique penetration enhancer

that is thought to provide benefit by

fluidizing stratum corneum lipids

and partially dissolving them.15 It is


Penetration Enhancers: Benefits and Challenges




used in clobetasol propionate 0.05%

spray (Clobex Spray, Galderma) to

encourage rapid penetration of corti-

costeroid into the treated skin.

Most penetration enhancing

excipients have the potential to be

irritating to the skin, depending

upon concentration and the other

inactive ingredients in a particular

vehicle.

Only relatively recently have for-mulators focused on modulating the

detrimental effects of penetration

enhancers by reducing or ameliorat-

ing the signs and symptoms of irrita-

tion. Review of three modern for-

mulations of benzoyl peroxide

(BPO)—an inherently irritating drug

—and clindamycin demonstrate how

vehicles may be formulated in

efforts to reduce the irritation poten-

tial.

Benzaclin (clindamycin, 1%, ben-

zoyl peroxide, 5%, Sanofi-Aventis)

contains micronized benzoyl perox-

ide in an aqueous gel with surfac-

tant and no non-volatile solvent.

Upon application, the micronized

BPO is deposited in the sebum-rich

follicle where it exerts it effects.

In Duac (clindamycin, 1%, ben-

zoyl peroxide, 5%, Stiefel)

micronized benzoyl peroxide is for-

mulated in an aqueous gel with sur-

factant, glycerin, a humectant to

minimize the desiccating effect of BPO, and the emollient dimethicone

to help moisturize the skin.

Acanya gel (clindamycin phos-

phate 1.2%, benzoyl peroxide 2.5%,

Coria Laboratories) contains a 2-fold

lower dose of benzoyl peroxide than

the other clindamycin/BPO prod-

ucts, yet laboratory evidence sug-

gests delivery of a similar amount

of BPO to the skin.16 This may be

an effect of low concentration

propylene glycol in the formulation

that helps to solubilize the BPO

microparticles and transports them

into the sebum.

The use of micrsopheres repre-

sents another approach to minimiz-

ing BPO-induced irritation.NeoBenz Micro (Intendis) entraps

micronized benzoyl peroxide within

polymeric sponges, offering slow

release of the drug over time. Slow

release of benzoyl peroxide through

microspheres is shown to reduce

irritation and minimize percuta-

neous absorption.17,18

Other attempts to minimize the

irritancy associated with BPO

while enhancing efficacy have

focused on solubilizing the drug. A

gel and lotion formulation

(ClenziDerm, MD, Obagi Medical

Products) features chemically

micronized, solubilized BPO mole-

cules to ensure even distribution in

the vehicle. In clinical trials com-

paring solubilized BPO gel to a

non-solubilized BPO/clindamycin

combination formulation, the solu-

bilized gel produced a greater

reduction in non-inflammatory

lesions at weeks 1 and 2 and an

equivalent reduction in inflamma-tory lesions at week 12. Solubilized

BPO is shown to produce a greater

reduction of colony forming units

of P. acnes compared to combina-

tion BPO/clindamycin.19

Ethanolic foam vehicles that

dissolve at body temperature

(Olux and Luxiq, Stiefel) not only

provide good spreadability and

cosmetic elegance, but also

enhance delivery of corticos-

teroids compared to other tradi-

tional formulations. The mecha-

nism to enhance penetration is the

creation of a supersaturated drug

solution in the propylene glycol-

rich secondary formulation

remaining on the skin after evapo-ration of the alcohol and propel-

lants. Supersaturation provides a

driving force for drug delivery

into the skin. Despite good overall

tolerability with original ethanolic

foams, a newer foam vehicle

(Olux E, Stiefel) features emol-

lients that counter the drying

effect of the ethanolic foam,

thereby hydrating the skin and

providing a lubricant film to coun-

teract sensations of stinging, burn-

ing, and dryness related to

ethanol.20

In the case of Metro 1 (metron-

idazole 1%, Galderma), metronida-

zole is not very soluble in water

or oil, so the molecule was formu-

lated inside a dextran ring

(Betadex NF or beta cyclodextrin)

to which niacinamide was added

in order to keep 10mcg/g in solu-

tion. Given the physicochemical

characteristics of metronidazole,

optimal delivery would be predict-ed from a solution rather than a

suspension of the active ingredi-

ent. Niacinamide is further shown

to improve skin hydration and

barrier function.21 Low concentra-

tions of glycerin in the formula-

tion enhance percutaneus absorp-






tion and provide humectant

effects. Betadex has a polyhydric

hydrophilic surface (to enhance

solubility and moisturize the skin)

and hydrophobic core that encap-

sulates the metronidazole mole-

cule. This newer formulation

enables once-daily dosing of a

higher concentration of metronida-

zole than had previously been

available, and with improved tol-

erability.

T he classification of topical

dosage forms has recently

been updated and codified.While some terms commonly

used to describe specific vehicles are

actually developed for marketing

purposes, FDA recognizes eight topi-

cal dosage forms: Solution,

Suspension, Lotion, Paste, Gel,

Ointment, Cream, or “Other,” which

includes foams, aerosols, powders,

patches, etc.22 (See Table 1.)

The clinical significance of these

classifications varies; however there

are many situations where the vehi-cle matters. Clinicians may favor

certain dosage forms for specific

uses, and they often ascertain the

benefits of various forms from clini-

cal study data, practical experience,

product package inserts, manufac-

turer's materials, and peer educa-

tors. For conditions such as atopic

dermatitis, psoriasis, and contact

dermatitis with unique skin reactivi-

ty, the improper choice of vehicle

can impact therapeutic outcomesleading to signs and symptoms of

cutaneous irritation, poor patient

compliance, and production of aller-

gic contact dermatitis due to a pre-

servative.

An occasional mismatch between

the official designation of a product

and its practical appearance may

have a significant impact on patient

Topical Dosage Forms

“Other”:

Formulations that are

not liquid or semisolid fall

into this category, which

includes aerosols,

powders, etc.

Solutions:

Clear and homogeneous

Suspensions:

Solids dispersed in liquids

Lotions:

Emulsions

>50% water and other

volatiles

Gel:

Solution or colloidal

dispersion stiffened with

a gelling agent

Cream:

Emulsion

<50% water and other

volatiles

Ointments:

More than 50% of hydro-

carbons, waxes or PEG

and less than 20% water

and volatiles

Pastes:

Contain 20-50% dispersed

solids

Cream:

One or both does not

apply:

• More than 50% of hydro-

carbons, waxes or PEG

• Less than 20% water and

volatiles

SemisolidsLiquids

Is it Pourable?

Non-liquid, Non-semi-solid

YesNo

Table 1. Topical Dosage Forms forDermatological Applications

(Based on Buhse L, et al. International Journal of Pharmaceutics; 295: 101-112.)





care. Despite its dosage form desig-

nation, Diprolene Lotion 0.05%

(betamethasone dipropionate,

Shering Corp.) would be categorized

as a solution under today's FDA

naming system, as the vehicle is in

fact a clear hydroalcoholic solution

intended for scalp treatment, and

not a fluid emulsion of oil and

water (i.e. lotion).

These dosage form classificationsare particularly relevant to the

development of generic challengers

of innovator formulations. To apply

for marketing approval from the

FDA, a generic formulation must

challenge a specific existing product

(active drug, concentration, and

dosage form). For example, if the

FDA had only approved a New Drug

Application (NDA) for triamcinolone

acetonide 0.1% cream , and no other

dosage form were yet available; a

generic manufacturer could only

challenge the branded product with

a 0.1% cream dosage form via the

inexpensive generic approval route

with an Abreviated New Drug

Application (ANDA). Triamcinolone

0.1% in any other dosage form

(lotion or gel) would need to go

through the full NDA and review

process in this hypothetical case. For

this reason, and because choice of

vehicle matters to dermatologists for

unique and clinically important rea-

sons specific to the individual

patient, non-dermatologists, pharma-

cists, and insurance providers

should not substitute differentdosage forms or vehicles than the

one prescribed by the dermatologist.

Gels and foams, both of which

will be further addressed in the sec-

ond installment of this series, are the

dosage forms that have probably wit-

nessed the greatest advancement in

recent years. Alcohol-based gels,

once considered appropriate only for

oily skin, have largely been replaced

by hydrogels and nonaqueous gels,

changing the way that clinicians

view gels and broadening their use.

The term “hydrogel” is a descrip-

tive marketing term. Although it is

not an official designation recog-

nized by the FDA, it does have a

technical meaning in the industry.

A hydrogel has low residue, is non-

sticky when applied, has a high

cosmetic acceptability, is free of

acetone, alcohol and significant lev-

els of harsh solvents, and has a

very high water content. In this

sense, the term describes the con-

sistency and appearance of the

hydrogel, as well as potential bene-

fits to the patient. These formula-

tions do not sting or burn and areassociated with a lower incidence

of adverse events compared to alco-

hol-based gels. Typically, a humec-

tant ingredient is incorporated to

provide what is called a “pillow

effect.” Whereas traditional gels dry

down very quickly and make the

skin feel tight, the water-retention

properties of the humectant in a

hydrogel impart a softness to the

skin.

Many of the gel formulations

marketed today are hydrogels, with

a few exceptions. Generic tretinoin

gel 0.025% is an alcohol gel, and

Xolagel (Ketoconazole 2%, Stiefel) is

an anhydrous gel, different from a

hydrogel.

Formulating for Special Populations

In addition to the drug to be

delivered, the site of drug

activity, and the anatomic sitetargeted, formulators must also

consider any specific needs and

preferences of the population to

be treated. Data and experience

show that factors such as difficul-

ty of use, messiness, odors, and

staining all affect patients' prefer-

ences.24 Patient age is a potentially

significant consideration. While

the structure and function of theskin of a child may not differ sig-

nificantly from that of an adult on

a cellular basis,25 there is an

important physiologic difference,

due to the higher ratio of skin sur-

face to body mass in children.

This is particularly relevant to the

treatment of widespread skin dis-

ease and use of topical corticos-

teroids (a more complete discus-sion of factors associated with cor-

ticosteroids begins on p. 12).

Due to regulatory requirements

coupled with caution on the part of

investigators, few formulations are

studied in patients under age two

(or over age 65; See Sidebar: Age





“Cosmetically elegant” is a subjective, descriptive term with a

marketing rather than regulatory or classification function. For a

cosmetic product to be considered cosmetically elegant, it must

feel good, look good, and smell good (based on fragrance con-

tent). For topical drug products, the issue of a pleasing fragrance

is generally not as significant; however the formulation should

feel good and not have an unpleasant appearance (such as odd

color or grainy consistency). A cosmetically elegant drug formu-

lation hopefully will at least not smell bad, although some topi-cal agents and excipients have a scent that is unpleasant to

many patients.

With few exceptions (such as DermaSmooth [fluocinolone

acetonide Topical Oil, 0.01%, Hill Dermaceuticals] and Renova

[tretinoin cream 0.02%]), fragrances are not added to topical

drug formulations, although masking agents (typically neutraliz-

ing fragrances) can be use—-leading to an “unscented” or “fra-

grance-free” claim. Sodium sulfacetamide and sulfur combination

products for acne and rosacea usually have an unpleasant and

lingering odor. Rosanil wash (sodium sulfacetamide 10% and sul-

fur 5%, Galderma) however, contains masking agent that elimi-

nates the sulfurous odor.

Fragrances are the most common family of allergens to cause

contact dermatitis from cosmetics. Of the roughly 2,500 fra-

grancing chemicals that are used in the US, about 100 are

known or reported to be contact sensitizers. The common sensi-

tizers used for patch testing are said to be found in a significant

percentage of cosmetic products. Yet, estimates suggest that, at

most, four percent of the general population shows positivepatch test to these ingredients.23

Clearly, identifying clinically relevant fragrance sensitivity can

be a challenge. Nonetheless, patients known to be allergic

should avoid cosmetics and topical drug products containing

sensitizing fragrances, including masking fragrances. When a

patient has a known fragrance allergy, the practitioner may spec-

ify on the prescription “Brand necessary: Patient allergic to fra-

grance.” In such cases, it is unlikely that the insurance company

or pharmacist will be able to identify a suitable generic product

to substitute.

Cosm et ic Eleg ance

Restrictions on Prescribing), so

direct evidence of safety and effica-

cy has been lacking. Nonetheless,

consideration of the available data,

empirical evidence, and clinical

experience typically guide the safe

use of many topical formulations in

patients as young as full-term

infants. An exception may be the

pre-term infant where the barrier is

not fully formed and significantly

increased percutaneous absorption

and toxicity have been well-docu-mented.26

Diaper wearing can affect skin

barrier function due to occlusion

and potential for tissue macera-

tion, and in children there may be

some enhanced drug absorption at

certain anatomic sites compared

to adults. For this reason caution

is advised in treating the diaper

area with topical drugs on a

chronic basis. Practical considera-

tions, such as tolerability and ease

of application, may also influence

the treatment of children. Parents

may be more likely to comply

with applications of formulations

that are spreadable, soothing, and

can be applied quickly, (i.e.,

hydrocortisone butyrate 0.1%

lotion (water-in-oil emulsion)[Locoid Lotion, Triax

Pharmaceuticals]).

A parent is not likely to apply

to a child's skin a formulation that

causes stinging or burning. For

example, when topical hydrocorti-

sone 1% was formulated with

urea 10%, it offered efficacy

equivalent to a mid-potency

steroid for atopic dermatitis, but it

had low tolerability.28

Ethnic i ty . Although largely not

studied, and while significant dif-

ferences may not be evident on the

cellular level, practical considera-

tions may influence management of

patients based on ethnicity.

Petroleum jelly has been shown to

reduce transepidermal water loss

by 98 percent,29 making it a favor-able occlusive moisturizer or for-

mulation base. While some will not

tolerate use of a petrolatum-based

ointment to some anatomic sites for

cosmetic reasons, some patients

prefer petrolatum-based products at

some anatomic sites. Clinicians



Roughly only one-fifth of all drugs on the US market are

labeled for use by infants and children, and only 30 to 40 per-

cent of drugs have an indication for use in children under age

12. Consequently, one study found, 62% of outpatient pediatric

visits (0-17 years of age) in the US resulted in off-label prescrib-

ing (67% of pulmonary and dermatologic medication prescrip-

tions were off-label).27 Prescribing information for currently-mar-

keted topical corticosteroids may contain age limits (from a

lower limit of three months up to 18 years of age and often an

upper limit of 65 years of age).

These apparently arbitrary age limits are artefacts of the regu-

latory review and approval process. Trial designers typically

excluded patients over age 65 because the increasing risk of

death due to cardiovascular or other natural causes inherent in

this older population increases the risk that a subject may die or

experience a serious medical event during the trial. Even if the

death or event is not related to therapy, it is thereafter associated

with the drug labeling.

Until fairly recently, FDA had not required

pediatric testing of drugs subject to the

review of an NDA. Since December 1998,

when FDA made the pediatric rule effective,

drug manufacturers are now required to

conduct some studies of new products in

the pediatric population or obtain a “pedi-

atric waiver.”The extent of studies conducted

in the pediatric population for NDA approval

these days depends on prevalence of the

disease at various ages within the pediatric population, the

extent of the required animal safety studies needed to support

such pediatric testing, and negotiations between the manufac-

turer and FDA. Topical corticosteroids are commonly used in

subjects younger than two, e.g., in the management of atopic

dermatitis. FDA currently requires testing of corticosteroids in

pediatric subjects if the labeled indication includes atopic der-

matitis. The clinical safety of some corticosteroid products have

exteneded to children as young as two years of age, while others

have data down to three months of age. The differences in

pedictric age limitations among products is the result of the

labeling sought by the particular manufacturer and actual data

supporting safety in that age cohort. Studying the HPA axis

effects of topical corticosteroids in very young patients builds a

foundation of data to support their safe use in children and also

helps to assure access to therapy for very young patients.

Age Rest r ic t ion s on Prescr ib i ng



anecdotally have reported regional

and ethnic trends in certain vehicle

preferences.Ethnic differences in clinical

response to topical therapies have

been documented but are poorly

understood. In the original trials for

tacrolimus ointment 0.03%

(Protopic, Astellas) for adult atopic

dermatitis, active treatment was not

superior to vehicle in African-

American adults. Tacrolimus was

superior to vehicle in Caucasianadults, and there was no difference

in response between African-

American and Caucasian children.30

Wedig and Maibach reported a

34 percent lower in vivo absorp-

tion of 14C-labeled dipyrithione

following topical application to

four male African American sub-

jects relative to four male

Caucasian subjects.31 However,Lotte et al., using the same

methodology, reported no statisti-

cally significant differences in the

in vivo absorption of 14C-benzoic

acid, 14C-caffeine, and 14C-acetyl-

salicylic acid following topical

application to African American

Examples of Topical Corticosteroids with Specific Age Allowances Below 2 Years

3 Months or older

• Desonate Gel (desonide), 0.05%; Intendis

• Derma-Smoothe/FS Topical Oil (fluocinolone acetonide), 0.01%; Hill Dermaceuitcals

• Locoid Lipocream/Lotion (hydrocortisone butyrate), 0.1%; Triax Pharmaceuticals, LLC

• Verdeso (desonide) Foam, 0.05%; Stiefel

1 Year or older

• Aclovate Cream or Ointment (alclometasone dipropionate), 0.05%; GlaxoSmithKline

• Cutivate Lotion (fluticasone propionate), 0.05%; PharmaDerm

• Cutivate Cream (fluticasone propionate), 0.05%; PharmaDerm





T opically applied medications

can reach the US market in

one of three ways: a new

drug application (NDA), an

abbreviated new drug application

(ANDA) for generics, or by com-

pliance with an OTC Monograph

as an over-the-counter (OTC or

non-prescription) product (see

Sidebar: OTC Monograph). Other

topically applied products are

either cosmetics, which FDA doesnot approve for marketing, or

devices granted 510K marketing

clearance. (See “Divining the

Details of Device Clearance,”

available online at

VehiclesMatter.com).

Drugs that had been marketed

prior to passage of the Food, Drug,

and Cosmetics Act in 1938, were

permitted to remain on the market.

Ultimately, some were submitted for

approval in NDAs in their existing or

in new formulations. Others were

shown to be ineffective or dangerous

and were abandoned. In 1968, FDA

established “Drug Efficacy Study

Implementation” or DESI with the

aim of evaluating drugs that had not

yet undergone clinical trials andreview. About 160 drugs have still

not been reviewed yet are available

on the market. Known as DESI

drugs, many are still used in derma-

tology-coal tar, sulfur, sodium sulfac-

etamide, and hydroquinone, among

them. Sometimes these drug prod-

ucts based on very old active ingre-

dients are known as “grandfathered”

drugs or unapproved prescription

products.

Since the passage of the Food,

Drug, and Cosmetics Act of 1938,

FDA has established strict process-

es for the review and approval of

new drugs. FDA approves a specific

drug formulation on the basis of a

New Drug Application; it does not

approve a chemical entity or com-pound. For example, although the

FDA had approved oral dapsone

more than five decades earlier, top-

ical dapsone gel could not come to

market based on that filing. An

NDA for dapsone gel 5% was sub-

mitted to FDA with data supporting

Drug Approval and the Case of Corticosteroids

(n=6 to 8 depending on com-

pound), Caucasian (n=9), and

Chinese American (n=6 to 7) sub-

jects.32 Clearly any potential ethnic

differences in skin penetration

may well be formulation as well

as compound dependent.

Geograph ic skin diff erences.

Geographic skin differences may

also exist as a result of environment.

For example, differences in humidi-ty in the Southwestern United States

compared to the North East could

impact skin hydration, TEWL, and

barrier function.33,34

Gender . The influence of gender

on topical therapy is an important

consideration and a relatively new

area of research, with evidence

suggesting differences in male and

female responses to certain topical-

ly applied drugs.35,36

Ski n Chan ges th roughou t Lif e.

While skin structure and function

may not vary significantly based on

age, certain characteristics of the

skin change with time. Following the

significant change in the skin of a

newborn as the individual adapts

from the watery millieau of the

amniotic sac to the natural environ-ment, the next significant change in

the skin occurs around puberty.37

Additional changes occur gradually

over time, so that some variation in

the skin may be seen when com-

pared from decade to decade of life.

These changes can influence the

delivery and activity of topical

drugs.

Prepubertal skin, for example,

does not produce significant

amounts of sebum, thus the

biofilm is considerably different

from that of a teen. Any topical

formulation applied to the skin

mixes with and is affected by the

natural biofilm. With age the epi-

dermis thins and the level of natu-

ral moisturizing factors decreases;

diminished protease levels lead todecreased rates of desquamation,

potentially easing the absorption

of drugs via the intercellular path-

ways. Vehicles with moisturizing

properties (i.e., those containing

emollients and humectants) may

be clinically desirable for deliver-

ing topical drugs in the geriatric

population.





its strength, dosage form and new

indication.

The costs associated with bring-

ing a new prescription product to

market have risen significantly over

the past decade. The development

costs for a new chemical entity

(NCE) as a dermatological, starting

with formulation development

through NDA approval, is currently

estimated to be $40-50 million ormore, exclusive of the significant

research costs associated with dis-

covery and synthesis of the com-

pound. Because a new formulation

containing an already-approved

drug for a new indication, strength,

or dosage form can bypass some

safety studies, development costs

may be decreased to around $15-25

million. Combination drug products

for dermatologic use (a clin-

damycin/benzoyl peroxide formula-

tion, for example) can be expected

to be intermediate in cost. The

developer and/or intended marketer

must demonstrate that the new

drug formulation is safe and effec-

tive for the intended indication in a

systematic step-wise manner.

Among the many aspects that must

be addressed during the typical

four to seven year development

period of the vehicle (from initial

design to market approval) are sta-

bility and lack of unsafe levels of impurities and degradation.

A generic drug product seeks to

match an approved drug formula-

tion in terms of active ingredient,

concentration, and dosage form.

Besides chemistry documentation

(e.g., demonstration of stability),

such products must demonstrate

bioequivalence to the Reference

Listed Drug (RLD) or innovator

through relatively inexpensive tests.

Bioequivalence signifies that “the

rate and extent of absorption are

not statistically different when

pharmaceutical equivalents are

administered to patients or subjects

at the same molar dose under simi-

lar experimental conditions.”In order to demonstrate bioe-

quivalence to an oral RLD, a gener-

ic oral formulation must demon-

strate equivalent bioavailability

through comparable plasma con-

centrations. For topical medica-

tions, methods for demonstrating

bioequivalence are more complex

than for oral products and contro-

versial. For example, plasma con-

centrations are usually very low

and fail to demonstrate that a topi-

cal drug is available at the neces-

sary site of activity. There are three

ways a generic topical product can

meet the bioavalibility require-

ment: 1.) by a bioequivalence waiv-

er from FDA (commonly allowed

for solution dosage forms), 2.) by a

show of “equivalence” of a corticos-

teroid in the vasoconstriction bioas-

say (described in more detail

below), or 3.) by a demonstration

of clinical bioequivalence for all

non-corticosteroid topical productsin a three-arm study (generic prod-

uct v. RLD v. vehicle). Clinical

measures are variable, difficult to

control for, and may lack sensitivi-

ty. Thus, such clinical bioequiva-

lence trials are quite large and

expensive.

If the generic formulation

demonstrates bioequivalence, its

safety and efficacy are assumed to

be equivalent to those of the inno-

vator. The generic product must

meet most of the same chemistry

and pharmacologic criteria required

of the RLD, including establishing

a stability-based shelf life. Costs to

bring generic topical formulations

to market today can be from$500,000 to $1.5 million, unless a

clinical bioequivalence study is

required, thus increasing the devel-

opment cost to an estimated $4-6

million.

Topical corticosteroids are

among the drugs most commonly

prescribed by dermatologists and

represent a tremendous proportion

of the generic topical prescription

market and therefore represent a

suitable focus for exploring generic

drug approvals. The US topical cor-

ticosteroid market was $1.5 billion

in 2009 as a result of more than 35

million prescriptions, of which

slightly more than 90% were for

generics.

The standard bioassay adopted by

FDA for demonstrating bioequiva-

lence of topical corticosteorids is the

vasoconstriction assay using the

Area Under the Effect Curve or

AEUC. This bioassay is based on the

findings of Stoughton and McKinziethat corticosteroids cause skin

blanching and that this surrogate

pharmacodynamic response is relat-

ed to potency and clinical efficacy.

FDA has adapted the original

bioassay to serve as a bioequiva-

lence assay with specific test




parameters. A chromameter is used

to measure skin blanching effect

over an established period of time

as elicited by a topically applied

test formulation (T), the reference

drug (R), and at untreated control

sites.38 To establish bioequivalence,

FDA requires that the 90% confi-

dence interval for the ratio of the

AUEC due to the test product and

the AUEC due to the reference

product does not differ significant-

ly; significance is defined as 20%.As such:

• The lowest limit for T/R =

80/100 or 80%.

• The maximum limit for R/T =

100/80 or 125%.

There are concerns about the

clinical significance of the

-20/+125 variability permitted for

bioequivalence measures. This wide

percentage variability in the deliv-

ered dose of an innovator compared

to its generic can be expected to cor-

relate with a difference in clinical

efficacy. Possibly more concerning is

the potentially significant difference

between two generics formulations.

Suppose challenge product A tests in

the -15% range, relative to the inno-

vator, while challenge product B

tests in the +20% range. The poten-tial clinical implications for a patient

switched from A to B—such switch-

es occur frequently—are obvious.

Furthermore, while bioassay data

demonstrate the effects of a topical

corticosteroid at the conclusion of a

set period of time after a single

micro-dose, it does not provide clini-

cally important information, such as

minute-to-minute and hour-to-hour

pharmacodynamics of a drug;

effects of multiple doses on the skin;

or the impact of the physical proper-

ties of the generic vehicle on patient

compliance. The latter two can vary

significantly based on the vehicle.

Application time is an important

consideration in topical therapy, asa drug must be given the opportu-

nity to absorb through the stratum

corneum. In clinical practice, some

vehicles have been found to virtu-

ally slide off the skin, permitting

little time for drug absorption.

Application site matters, as well. If

not properly formulated, a vehicle

applied to the hands, for example,

may be transferred rather quickly

to objects or other anatomic sites

or washed off. Two formulations

could have comparable AUECs as

demonstrated in a laboratory, but if

one does not remain on the affect-

ed skin for an adequate time, the

clinical implications are obvious.

Unfortunately, FDA requires no

test for clinical utility of the vehi-

cle of a generic dosage form.

As noted, except for the case of

bioequivalence waivers, generic

manufacturers must match the

dosage form but not necessarily the

excipients that comprise the vehi-cle. In order to establish equivalen-

cy, formulators may incorporate

high proportions of penetration

enhancers in their products to dis-

rupt the stratum corneum and

encourage drug absorption. There

is no requirement for assessing the

FDA oversight of OTC drugs differs significantly from that for prescription drugs. The

Office of Nonprescription Products maintains a list of more than 80 therapeutic cate-

gories of OTC drugs. The Center for Drug Evaluation and Research oversees these

agents to assure they comply with safety and labeling. The OTC Monograph outlines

the permitted active ingredients, dosages appropriate for OTC marketing, indications,

and label language. The OTC Monograph, in a sense, provides a recipe for OTC prod-

ucts, with rare specifications or restrictions on dosage form or formulations. Any manu-

facturer who creates a formulation under the parameters outlined and with the labeling

indicated is able to bring that formulation to market without FDA review and approval.OTC products must comply with the Monograph and Good Manufacturing Practices

(GMP) including documentation of stability.

Among OTC Monograph categories, which include antacids and aphrodisiacs, are multiple

categories of relevance to dermatology:

o Acne (benzoyl peroxide, salicylic acid) o Antifungals

o Antimicrobials o Antiperspirants

o Dandruff/seborrheic dermatitis o External analgesics (poison ivy, oak, sumac)

o Pediculicides o Sunscreens

o Skin protectants (diaper rash, cold sores, insect bites, poison ivy, oak, sumac

o Wart removers

OTC M on og raph




important local safety parameters

of irritancy and skin barrier func-

tion of generic corticosteroid

creams, lotions, gels, ointments or

foams.

The laboratory assays described

above are intended to demonstrate

bioequivalence—that is, they show

that the formulations provide simi-

lar bioavailability of active drug at

specific time points. Bioequiv-alence is one component of

“Therapeutic equivalence,” a term

which would seem to suggest that

two formulations will have equiva-

lent efficacy in clinical use.

However, according to FDA, head-

to-head clinical trials of formula-

tions to treat active disease in

human subjects are not required

to demonstrate therapeutic equiv-

alance.

Generic corticosteroid formula-

tions need not repeat HPA axis test-

ing, which is required of innovator

or reference drugs. Although HPA

axis suppression is rarely a signifi-

cant clinical concern for adults,

HPA axis suppression in children

can have numerous systemic side

effects, including an effect on long-

term growth, and bone formation.

Increasingly, evidence suggests that

the vehicle can help to modulate

rate and extent of systemic absorp-

tion associated with topical corti-costeroid delivery.

Given advancements in mole-

cule engineering and formulation

development, most modern refer-

ence low-potency topical corticos-

teroids are not associated with sig-

nificant risks of HPA axis suppres-

sion, therefore claims of safety

based on comparison of HPA axis

results for reference formulations

within the same potency class may

be misleading. Yet, when modern

formulations are compared to older

formulations (especially consider-

ing that pre-clinicaltrials.gov some

results were never published; See

Sidebar: ClinicalTrials.gov),

enhanced safety is evident.

Characteristics of the vehicle

can profoundly modulate the localand systemic safety (as previously

described) as well as the potency of

a corticosteroid. For example,

betamethasone dipropionate 0.05%

is characterized in four different

potency classes, depending on the

vehicle (See Table 2).

Conclusion The development of an appropri-

ate topical formulation for a given

active drug is a complex, time-

consuming, and costly process.

Nearly every clinical trial undertaken in the US today (and a majority of those conduct-

ed around the world) is registered at ClinicalTrials.gov. An important beneficial conse-

quence of this public registry is that it has created a checks-and-balances system within

the clinical studies community. Studies are listed during early phases and researchers are

required to post updates (including discontinuation) and to provide access to published

results. In the past, researchers could simply bury sub-optimal or unexpected results

because few people knew that a trial was ever underway. Now, because every trial is

recorded in a searchable public database, researchers today do not have that liberty.

ClinicalTrials.gov is a project of the US National Institute of Health (NIH) administered

through the National Library of Medicine (NLM) in collaboration with all NIH Institutes and

the FDA. The stated mission of the website is to provide “patients, family members, health

care professionals, and members of the public easy access to information on clinical trials

for a wide range of diseases and conditions.”The database was mandated in the Food and

Drug Administration Modernization Act (1997) which required the Department of Health

and Human Services, through the NIH, to establish a registry of clinical trials for both fed-

erally and privately funded trials.

The site is intended to help potential participants identify enrolling studies as well as to

disseminate information about trials. ClinicalTrials.gov currently contains 85,508 trials

sponsored by the National Institutes of Health, other federal agencies, and private indus-

try. Studies listed in the database are conducted in all 50 States and in 171 countries.

ClinicalTrials.gov

Table 2. BetamethasoneDipropionate 0.05%Potency Categorizations

Class I

Diprolene Cream, 0.05%

Diprolene Ointment, 0.05%

Class II

Diprolene Cream AF, 0.05%

Diprosone Ointment 0.05%

Class III

Diprosone Cream 0.05%

Class V

Diprosone Lotion 0.05%




Yet this laborious and multi-step

process is necessary to assure effi-

cacy, enhance compliance, and

decrease the possibility of adverse

events. For a field such as derma-

tology that has seen the introduc-

tion of relatively few new chemi-

cal entities in recent years, new

therapeutic development initia-

tives have largely focused on

improving vehicles to optimize

treatment. Part II of this series

(June 2010) will further investi-

gate specific dosage forms used in

dermatology with an emphasis on

vehicle development challenges

and the potential for real clinical

benefits. ■

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ide gel with benzoyl peroxide/clindamycin: final data from a multicenter, investigator-blind, randomized study. J Drugs Dermatol. 2009 Sep;8(9):812-8.

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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


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