MAY 2010
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`CoJ>v1uc;111 © 2010
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`s53
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`V01 UME 9 • lsSUE 5 (SUl'l'LEMENT)
`
`joURNi\L OF D1tucs IN Dl'IU\11\TOLOCY
`
`Optimizing Acne Therapy With Unique Vehicles
`
`Leon Kircik MIY and Adam Friedman MDh
`'Indiana University, Indianapolis, IN; Physicians Skin Care, l'LLC:, Louisville, KY
`"Division of Dermatology, I )epartmcnt of Medicine, Albert Einstein College of Medicine, Uronx, NY
`
`The science of cutaneous drug delivery is focused on overcoming the major force of resistance to drug penetration and permeation(cid:173)
`the stratum corneum. Acne vulgaris is a multifactorial disease of the pilosebaceous unit. resulting from abnormalities in sebum
`production, follicular epithelial desquamation, bacterial proliferation and inflammation. Topical treatment of even mild-moderate acne
`requires combination topical therapy, yet often systemic therapy is needed to ultimately confer an acceptable clinical endpoint. New
`delivery systems have emerged in response to the limited routes of entry and therefore efficacy of topical regimens. The unique
`physical and optical properties of micro/nano encapsulation of known therapeutics such as benzoyl peroxide and tretinoin allow for
`both improved efficacy while minimizing issues of compliance and adverse events. Vehicles that offer both inherent biological re(cid:173)
`activity and permeation enhancement have also been shown improvement over the current armament of topical drug delivery. This
`current and exciting path of topical drug development will likely be continued with investigative vigor.
`
`,IN:f.RODl:JGT-IONl!I
`
`T he stratum corneum is arduous impediment to topical
`
`drug delivery, making localized therapy a challenge. The
`hydrophobic barrier of stratum corneum, the "brick and
`mortar" of the epidermis, places special demands on compounds
`intended for this unique target.The impenetrability of stratum cor(cid:173)
`neum is in part due to the insoluble nature of corneocytes-a state
`resulting from extensive cross linking of both the cell envelope
`and intracellular proteins. 1 Most topical drugs cannot cannot even
`bypass this outer barrier, let alone pass from one epidermal layer
`to the next. However, both the active ingredient and/or solvent can
`be altered to enhance delivery to the target site. 2
`
`To further understand the complexities of topical drug delivery,
`several key terms need defining as they are often used inter(cid:173)
`changeably. First, penetration refers to the entry of into a particu(cid:173)
`lar skin layer, whereas permeation refers to a compound moving
`from one skin layer to another. Absorption, a term often used to
`describe various avenues of therapeutic uptake, actually is de(cid:173)
`fined by the topically applied drug being taken up by blood ves(cid:173)
`sels in the skin in order to enter systemic circulation. 1 However,
`systemic absorption is usually not the intended endpoint, rather
`topical therapy is generally used by the physician to provide high
`local impact without the potential side effects associated with,
`for example, an injectable or oral route of administration.
`
`Structure and Function of the Skin
`The skin is an extraordinary organ, serving numerous functions
`ranging from barrier protection to overseer of fluid/electrolyte
`homeostasis.3 The skin is divided into three distinct yet inter(cid:173)
`twined levels: epidermis, dermis and panniculus.The epidermis
`is composed of stratified, squamous keratinizing epithelium,
`which gives rise not only to the outermost protective layer,
`the stratum corneum, but also is the source of several key cu-
`
`taneous structures such as the pilosebaceous units, the nails
`and sweat glands. The stratum corneum can be considered the
`gatekeeper with respect to permeation of compounds into the
`body. The stratum corneum consists of the a nucleate, fully ker(cid:173)
`atinized corneocytes glued together by various epidermal lipid
`components, which provides for the "brick and mortar" anal(cid:173)
`ogy.4 With this in mind, it is easy then to appreciate that topical
`therapy is literally coming up against a brick wall.
`
`With respect to penetration, transport of topically applied ma(cid:173)
`terials occurs across the stratum corneum in largely passive
`diffusion and is reliant on the physiochemical properties of the
`permeating agent. 5 There are two major routes through which
`this diffusion across the skin can occur.The first is transappend(cid:173)
`ageal, relying of the natural imperfections in skin integrity asso(cid:173)
`ciated with hair follicles, and sweat glands. These openings can
`potentially allow topicals to bypass the low diffusivity of the
`stratum corneum. 6 Furthermore, this route may aid in the de(cid:173)
`livery of charged ions and large polar molecules that generally
`are slow to permeate through the stratum corneum. Ultimately,
`the choice of vehicle will affect its ability to utilize transfollicu(cid:173)
`lar penetration. The second pathway is through the epidermis
`itself, and is subdivided into two potential avenues, transcellu(cid:173)
`lar and intercellular.4 Hydrophilic compounds are likely to flow
`through the transcellular route, while lipophilic materials are
`preferential for the more round about intercellular route. It is
`believed that the latter pathway is the predominant route of en(cid:173)
`try for most topical therapies.7 Unfortunately, this pathway also
`serves as an impressive impediment for therapeutics intended
`for topical delivery.
`
`Topical Acne Therapy: Breaking Through the Wall
`Acne vulgaris is a multifactorial disease of the pilosebaceous
`unit, resulting from abnormalities in sebum production, folli-
`
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`Amneal v. Almirall
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`joUltNAL ()f' Dituc;s IN DERMATOLO(;y
`MAY 2010 • Vmul'vll 9 • IssuE 5 (Sul'l'IIMINI)
`
`s54
`
`L. I<.ircik,A. Friedman
`
`cular epithelial desquamation, bacterial proliferation and in(cid:173)
`flammation. The major classes of therapeutic agents are topi(cid:173)
`cal and systemic retinoids, antimicrobial agents and systemic
`hormonal drugs. Most dermatologists rely on a combination
`of topical therapies, or topicals with systemic therapies to
`treat acne, as no single topical acne therapy is effective in ad(cid:173)
`dressing all of the etiologic factors. Even with the combination
`of a retinoid with benzoyl peroxide (BPO), together attacking
`likely all four of the pathogenic features of acne, penetration
`of said products can limit efficacy. Strides have been taken to
`enhance the current armament of topical therapies through
`novel delivery vehicles.
`
`Benzoyl Peroxide (BPO)
`BPO is an organic compound in the organic peroxide fam(cid:173)
`ily. It consists of two benzoyl groups joined by a peroxide
`group, with a structural formula of [C 6H5C(O)] 2O2 • It is a lipo(cid:173)
`philic material, which serves as a boon, as it can localize in
`the lipid rich sebaceous follicles. Current BPO formulations
`are emulsions, which unfortunately have some limitations.
`These micronized solid particles, ranging from 5-1000 µmin
`size, are fairly large particles with poor solubility, ultimately
`resulting in diminished chemical activity. These formulations
`lack homogeneity in terms of consistency of the dissolution
`of particles throughout the formulation, and contain large
`clusters of BPO, providing for poor penetration and unsightly
`cosmesis following application. On electron microscopy the
`surface of the skin after application of a generic current BPO
`emulsion demonstrated poor penetration and extensive re(cid:173)
`sidual product on the skin surface.
`
`Benzoyl Peroxide (BPO) - New Vehicular Formulations
`In order to combat this deficiency, solubilized BPO has been for(cid:173)
`mulated, providing solid individual BPO molecules (-10 • prn) in
`solution. Solubilization is a clwrnicnl process which occurs be(cid:173)
`fore the BPO is incorporated into final product. This solubilized
`BPO formulation has both lipophilic and hydrophilic attributes,
`which aim to enhance penetration into the follicle and dissolve
`in sebaceous secretions.
`
`A second direction involves encapsulation of BPO in a Micro(cid:173)
`sponge"' delivery technology, designed to reduce irritation as(cid:173)
`sociated with this active ingredient. Microsponge technology
`has been used in the past to successfully deliver topical treat(cid:173)
`ments, such as Retin-A Micro"' and EpiOuin" Micro. In one study,
`it was demonstrated that BPO encapsulation in microsponges
`maximized the amount of time an active ingredient was present
`on skin surface or within epidermis with minimal penetration
`of active ingredients through the dermis. 8 This delivery system
`was also shown to enhance safety profiles by reducing irritancy
`potential while maintaining efficacy and extending product sta(cid:173)
`bility. Improved product aesthetic properties were also noted
`by the investigators.
`
`Taking this a step further, the success of the applies BPO Mi(cid:173)
`crosponge"" delivery system was investigated as a "wash-off"
`rinse. Clearly, a product such as this would only be relevant
`if the product displays substantivity-meaning it remains on
`the skin after rinsing. The persistence of effect is determined
`by the degree of physical and chemical bonding to the surface.
`Via confocal microscopy imaging, it was shown that wet skin
`areas treated with microsponge wash for 10-20 seconds then
`washed and dried had retained product within the follicular os(cid:173)
`tia. It was also found that this technology lived up to the name
`"sponge;' as the particles absorbed twice their own weight in
`sebum substrate. Recall in acne, there is an increase in sebum
`production from the multi-lobular sebaceous follicle. This excess
`sebum production can be due to a change in the response of the
`pilosebaceous follicle to androgen stimulation, increased andro(cid:173)
`gen circulation, or to both in combination.9 One of the interesting
`features of the microsponge polymeric porous particles is that,
`as they deliver the active ingredient, they in turn absorb excess
`surface sebum from the skin. In head-to-head comparisons, micro(cid:173)
`sponge outperformed other conventional cosmetic ingredients
`used as oil absorbers for sebum.
`
`As mentioned early, combination therapies have been the
`mainstay of topical therapy in order to address all pathogenic
`features of acne. So too can combination therapy be pursued
`to optimize the physical state of active ingredients in the for(cid:173)
`mulation. Lower concentrations of potentially irritating active
`ingredients can be used when incorporating a compatible
`moisturizing and drug delivery optimizing agent. For exam(cid:173)
`ple, combinations of clindamycin and BPO have been inves-
`
`FIGURE 1. Tretinoin micro is stable alone and in combination after UV
`light exposure.
`
`(cid:127) Tretlnoln + EBPO
`(cid:127) Retln-A Micro + EBPO II Retln~A Micro CBPO
`(cid:127) Retln-A Micro
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`Juui,NAL ()I 1)1,uc;s IN 1)1•1,MATOI ()(;y
`MAY 201 () • VmLJMI. <)
`lssuE 5 (Sui'l'LEMLNI)
`
`•
`
`s55
`
`L. Kircik, A. Fricd111a11
`
`11 Clindamycin/BPO fixed combination gel formula(cid:173)
`tigated. 10
`•
`tions were evaluated in a 21-day cumulative irritation study.
`This single-center, evaluator-blind phase 1 study in 35 healthy
`human volunteers assessed the cumulative irritation potential
`of formulations containing clindamycin phosphate 1.2% (CP) in
`combination with different concentrations of BPO. Test formu(cid:173)
`lations (5% BPO/1% CP, 2.5% BPO/1% CP and 1% BPO/1% CP)
`were applied under separate occlusive patches on the backs of
`subjects three times a week for three weeks. Sodium lauryl sul(cid:173)
`fate 0.3% was used a positive control. Each test application site
`was observed 48 hours (72 hours on weekends) post-application
`for signs of irritation or inflammation (a total of nine evalua(cid:173)
`tions). Assessment of skin irritancy was on a scale of O (no sign
`of irritation) to 4 (erythema with edema and blistering). A total
`irritation score for each subject and formulation was calculated
`by summing each of the subject's scores on each of the nine
`evaluation days. The mean cumulative irritation score for each
`test formulation was calculated as the sum of all subject's to(cid:173)
`tal irritation scores for a test formulation divided by 297 (nine
`evaluations x 33 subjects evaluated).
`
`Based upon the total irritation scores, all of these formulations
`were classified as slightly irritating under the occlusive test
`conditions. There was a 33% decrease in mean score the con(cid:173)
`centration of BPO from 5-2.5%. The benefits of further reducing
`the BPO concentration to 1% were surprisingly minimal. Over(cid:173)
`all, cumulative irritation scores increased in a dose-dependent
`manner with increasing benzoyl peroxide concentration, which
`is hardly surprising as this was described over 30 years prior. 12
`Therefore, it is clear that the development of delivery vehicles
`aimed at increasing penetration while decreasing irritation will
`continue to be the focus of novel acne therapies.
`
`Tretinoin
`For nearly 30 years, topical vitamin A acid or tretinoin has been
`the mainstay for condone targeted therapy. 13 Tretinoin efficacy
`
`is directly related to its ability to induce comedolysis and nor(cid:173)
`malize the maturation of follicular epithelium in order to prevent
`future comedone formation. 14 Although extremely efficacious,
`use can, similarly to BPO, be limited due to skin irritation. In
`addition, native tretinoin is photolabile and puts constrictions
`on dosing schedules. Therefore, a means to reduce these limi(cid:173)
`tations has been pursued. A microsphere polymeric technol(cid:173)
`ogy, allowing for controlled drug delivery onto the skin over
`time and in response to a trigger15·16 was developed for topi(cid:173)
`cal tretinoin. The system itself consists of porous microspheres
`that mimic a true sponge in structure and function. Each mi(cid:173)
`crosphere is formed by polymeric "ladders" that wrap around
`one another, forming multiple interconnecting spaces that serve
`as reservoirs for the drug. These reservoirs open on the surface
`of the microsphere. The biologically inert polymers used to
`make microspheres have been shown to be non-allergenic,
`non-mutangenic, non-irritating, non-toxic and non-biodegradable.
`Microspheres themselves are too large to permeate the stratum
`corneum, and, because tretinoin is not available for absorption
`until it leaves the microsphere, there is a lower accumulation
`in the epidermis. Furthermore, it was shown that encapsulated
`tretinoin was less susceptible to degradation following ultra(cid:173)
`violet light exposure (Figure 1 ). 16
`
`Vehicle Matters-Current and Future Directions
`Hydrosolubi/izing Agents (HSA-3™).
`Metronidazole 0.1 % topical gel is a once-daily formulation for
`treatment of rosacea. Well-controlled studies have shown that it is
`effective in the treatment of moderate to severe rosacea and well
`tolerated by varying evaluated subject types. The excellent tolera(cid:173)
`bility is probably due to the gel vehicle, which consists primarily of
`purified water (92%). Previously, metronidazole was only available
`as a suspension in a cream formulation. Unfortunately, creams
`often produce undesirable cosmetic effects such as greasiness,
`incompatibility with make-up and irritation of the skin for rosacea
`sufferers, due to emulsifiers and other excipients.
`
`FIGURE 2. Biopeptide aids penetration into the skin. a) Stratum corneum; b) Epidermis.
`
`35
`
`··--··----·--·· -----------
`
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`
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`
`(cid:143) carnoslne
`(cid:127) Pal-carnosine
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`0:
`
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`
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`
`0
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`Time (hours)
`
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`
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`
`Carnosine is an amino acid.
`
`Ccarnoslne
`(cid:127) Pal-carnoslne
`
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`
`6
`
`3 of 5
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`

`Jou,~NAL 01: DRUGS IN DEl~MA'l'OLOC:Y
`MAY 2010 • VOLUME 9 • ISSUE 5 (SUl'l'LEMENT)
`
`s56
`
`L. Kircik,A. Fried11m1
`
`Recently, a new gel vehicle capable of solubilizing greater con(cid:173)
`centrations of metronidazole was developed, making possible
`the cosmetically desirable attributes of a water-based gel that
`has the strength, safety and efficacy of 1 % metronidazole. This
`stable aqueous gel formulation containing 1% metronidazole
`was achieved with the novel combination of hydrosolubilizing
`agents (HSA-3™ ).17 This technology combines niacinamide,
`which has been shown to improve the appearance of facial skin
`texture by enhancing skin barrier function, Betadex (beta cyclo(cid:173)
`dextrin), a complexing agent to increase the aqueous solubility
`of highly water-insoluble and lipophilic drugs, and propylene
`glycol, a well known humectant and permeation enhancer. The
`metronidazole 1 % gel formulation assumes a unique configura(cid:173)
`tion, with an exterior hydrophilic surface that generates water
`solubility and enhances moisturization, and an interior hydro(cid:173)
`phobic cavity than encapsulates the metronidazole molecules
`and increases drug solubility. The betadex creates a core that
`enables the solubilization of metronidazole gel 1 %. 18
`
`Solvent Micro Particulate (SMP™)
`Topical dapsone gel 5% utilizes the advanced Solvent Micro
`Particulate (SMP™) delivery system, which was specifically
`designed to deliver dapsone topically. The product is an aque(cid:173)
`ous gel containing dapsone, diethylene glycol monoethyl ether
`(DGME), purified water, carbomer 980 neutralized to physiolog(cid:173)
`ic pH and methylparaben as a preservative.
`
`The SMP™ delivery system allows dissolved dapsone to per(cid:173)
`meate the stratum corneum to the epidermis. 1" It was found
`the properties of the diethylene glycol monoethyl ether
`(DGME) component helps facilitate permeation into the skin.2°
`Transcutol"' CG DGME is a hyclroscopic liquid that is freely
`miscible with both polar and non-polar solvents. Transcutol is
`considered a potential transdermal permeation enhancer clue
`to its non-toxicity, biocompatibility with skin and excellent
`solubilizing properties.
`
`Biopeptide Aloe Complex (BAC)
`Biopeptide Aloe Complex (BAC) is a complex combining native
`collagen fragment chain comprised of three amino acids (Gly(cid:173)
`His-Lys) to which palmitoyl is linked, and aloe peptides (Fig(cid:173)
`ure 2). The aloe polysaccharide is a pure aloe with a molecular
`weight range of 50-200 kDa with a mannose:galactose:glucose
`content of 40:1:1. The linked palmitoyl has both lipid and water
`solubility, which helps with cutaneous penetration.This material
`has been shown to increase fibroblast and collagen production
`as well as have anti-inflammatory and immune activity. 21 ,22
`
`'G0NGUUSIONl&I
`The science of cutaneous drug delivery has fought vigorously to
`overcome the major force of resistance to drug penetration and
`permeation-the stratum corneum. New delivery systems have
`emerged in response to the limited routes of entry. Micro/nano
`
`encapsulation of known therapeutics and the utilization of de(cid:173)
`livery vehicles that offer both inherent biological reactivity and
`permeation enhancement offer patients improved results when
`using topical therapy. It is clear that this path of development
`will continue to be pursued with investigative vigor.
`
`0•1~i@rt•MNl§:.f..it·:.J:1i>1
`
`Dr. Kircik is a consultant and investigator, and is on the Advi(cid:173)
`sory Board, for Va leant Pharmaceuticals, Intl., Warner-Chilcott,
`lntendis, Amgen, Inc., and Galderma Laboratories, LP. He is an
`investigator, speaker, and is on the Advisory Board for Allergan,
`Inc. He is a speaker, investigator, consultant, and is on the Advi(cid:173)
`sory Board for OrthoNeutrogena, SkinMedica, Inc., Stiefel Lab(cid:173)
`oratories, Inc., and Connetics Corporation. He is an investigator,
`consultant and speaker for CollaGenex. He is a consultant and
`is on the Advisory Board for Colbar. He is a consultant for and
`stockholder in Johnson & Johnson. He is an investigator and
`speaker for Leo, PharmaDerm, UCB, and Asteilas Pharma US,
`Inc. He is an investigator and is on the Advisory Board for Nano
`Bio and Ferndale Laboratories, Inc. He is a speaker and is on
`the Advisory Board for Genentech, Inc. He is an investigator for
`GlaxoSmithKline, PLC, Health Point, LTD, Medicis Pharmaceuti(cid:173)
`cal Corp., Navartis AG, Nucryst Pharmaceuticals Corp., Obagi,
`QLT, Inc., Pfizer, Ouatrix, TolerRx, Acambis, Asubio, Berlex Lab(cid:173)
`oratories (Bayer HealthCare Pharmaceuticals), Biolife, Breckin(cid:173)
`ridge Pharma, Centocor, Inc., Combinatrix, Coria, Dow Sciences
`and Dusa. He is a speaker for lnnovail, 3M, Serano (Merck Se(cid:173)
`rano International SA), Triax, Abbott Laboratories, and Dermik
`Laboratories. He is on the Advisory Board for Biogen-Idec.
`
`Dr. Friedman has no relevant conflicts of interest to disclose.
`
`al§ij;1§t4§~t@M~1.~-'-'!fii,J
`
`1.
`
`Huang X, Tanojo H, Lenn J, et al. VersaFoam: A novel vehicle
`for the delivery of topical corticosteroids. J Am Acad Dermatol.
`2005;53:S26-38.
`2. Pilnchilgnula R. Transdermal delivery of drugs. Indian J Pharmaco/.
`1997;29:1110-156.
`3. Walters KA and Roberts MS. Tho structure and function of ski11.
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`Thor Drug Carrier Syst. 1992;9:305·3li3.
`5. Roberts MS and Cross SE. Skin tran:;port. 111: Wiilturs KA, od.
`Dermatological and Transclorrnal For111ulations. Now York: M11rcel
`Dekker; 2002:89-195.
`6. Schaefer H, Redelmeier TE, Nohynek GJ. Pharrrncokinotics and
`topical applications of drugs. In: Freedberg IM, Eison AZ, Wolff H,
`et al, eds. Fitzpatrick's Dermatology in General Medicine. Vol 2.
`NewYork:McGraw-Hill; 2003:2313-2318.
`7. Matsuzaki K, lmaoka T, Asano M, et al. Development of a model
`membrane system using stratum corneum lipids for estimation of
`drug skin permeability. Chem Pharm Bull. 1993;41 :575-579.
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`JOURNAL OI' D1tuc;s IN DEltMATOLoc;y
`MAY 2010 • VmuME 9 • Issu1., 5 (Su!'l'LEMENT)
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`s57
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`L. Kircik,A. Friedman
`
`8.
`
`9.
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`Embil Kand Nacht S. The Microsponge"3 Delivery System: A topical
`delivery system with reduced irritancy incorporating multiple trig(cid:173)
`gering mechanisms for the release of active. J Microencapsulation.
`1996; 13(5):575-588.
`Saxena S, Nacht S. Polymeric Porous Delivery Systems: Poyltrap®
`and Microsponge''''. Delivery System Handbook for Personal Care
`and Cosmetic Products. In MR Rosen, ed. Technology, Applica(cid:173)
`tions and Formulations New York: William Andrew Publishing;
`2005:334-351.
`10. Bucks D, Sarpotdar P, Yu K, et al. J Drugs Dermatol. 2009;8(7):634-
`638.
`11. Gold MH. A new, once-daily, optimized, fixed combination of clin(cid:173)
`damycin phosphate 1.2% and low-concentration benzoyl peroxide
`2.5% gel for the treatment of moderate-to-severe acne. J Clin
`Aesth Dermatol. 2009;2(5):44-48.
`12. Kligman AM, Leyden JJ, Stewart R. New uses for benzoyl per(cid:173)
`oxide: A broad spectrum antimicrobial agent. Int J Dermatol.
`1977;16(5):413-417
`13. Kligman AM, Fulton JE, Plewig G. Topical vitamin A acid in acne
`vulgaris. Arch Dermatol. 1969;99:469-476.
`14. Lavker RM and Leyden JJ. An ultrastructural study of the effects of
`topical tretinoin on microcomedones. Clin Ther. 1994;14:,773-780.
`15. Bernerd F, Demarchez M, Ortonne JP, et al. Sequence of morpho(cid:173)
`logical events during topical application of retinoic acid on the rhino
`mouse skin. Br J Dermatol. 1991 ;125:419-425J.
`16. Nyirady J, Bennett M L, Advancement of tretinoin through the mi(cid:173)
`crosphere technology. Cosmet Dermatol. 2001, 14:22-24.
`17. Dow G. A Novel Aqueous Metronidazole 1 % Gel with Hydrosolubi(cid:173)
`lizing Agents (HAS-3™). Cutis. 2006;77(4 Suppl):18-26.
`18. Draelos Z. Assessment of skin barrier function in rosacea pa(cid:173)
`tients with a novel 1 % metronidazole gel. J Drugs Dermatol.
`2005;4(5):557-562.
`19. Thiboutot DM, Willmer J, Sharata H, et al. Pharmacokinetics of
`dapsone gel, 5% for the treatment of acne vulgaris. Clin Pharma(cid:173)
`cokinet. 2007 ;46(8) :697-712.
`20. Hadgraft J. Passive enhancement strategies in topical and trans(cid:173)
`dermal drug delivery. Int J Pharm. 1999;184(1 ):1-6.
`21. Davis RH, ParkerWL, Murdoch DP. Aloe vera as a biologically active
`vehicle for hydrocortisone acetate. J Am Pod Assoc. 1991 ;81 (1 ):1-
`9.
`22. Burnett B Mitchell CM. Antimicrobial activity of iodoquinol 1 %-hy(cid:173)
`drocortisone acetate 2% gel against ciclopirox and clotrimazole.
`Cut,s. 2008;82(4):273-80.
`
`ADDRESS FOR COIUtESPONDENCE
`
`Leon Kircik, MD
`Physicians Skin Care, PLLC
`1169 Eastern Parkway, Suite 2310
`Louisville, KY 40217
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