Treatment of PeriorbitalHyperpigmentation withTopical Vitamin KlVitamin A

Melvin L. Elson MD and Sergio Nacht, PhD

CosmeticCrD.,3~.....o0-

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Reprinted from the December issue

Cosmetic Dermatology

Quadrant Healthcom, Inc.

26 Main St., Chatham, NJ 07928

Copyright 1999. All rights reserved.

Printed in the U.S.A.

Treatment of PeriorbitalHyperpigmentation withTopical Vitamin KNitamin A

Melvin L. Elson MD and Sergio Nacht, PhD "

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Dark circles under the eyes is a very dis-concerting problem. Although productshave come on the market that purport to

.l ..~. treat this entity, no published study hasshown the efficacy of any treatment

modality. Part of the difficulty in developing a topicalagent to address this clinical entity is the lack of currentunderstanding as to the nature of the condition and thevarious factors that lead to its expression.

Periorbital and suborbital pigmentation in actuality canbe a combination of a number of different factors. It iscertainlyapparent that this problem is somewhat inher-ited, since the darkness is often present in very youngindividuals. There is also familial or ethnic tendency toan increase in melanin in this area that is manifested asyoung as teenage years and continues through life.Ad-ditionally, in some individuals there is a thinness in theskin of the lower lids, allowing for pigment as well asvessels to be visible through the skin. This particularproblem has not been correctable even with surgery upuntil this time.

Two factors combine to make this condition worsewith time: gravity and actinic damage. Gravity affects allaspects of the aging face, but particularly noticeable arethose areas that lack either subcutaneous substance orsurrounding support. This is particularly true of the pe-riocular area.1 The skin of the area moves downward,stretching and thinning it even more, allowing moreblood vessels and the orbicularis muscle to becomemore obvious, creating an increase in the darkness ofthe area.

Actinic damage plays a significant role in the aging ofskin, probably accounting for approximately 80% ofwhat is called aging.2 As the skin is exposed to UV,more redness, increased vascularity, broken vessels,dead end vessels and a thinness of the skin occurs? lnparticular, UVA significantly thins the skin and increases

Dr. Elson is the medical director of The Dermatology Cen-ter; Ine in Nashville, TN and founder of the Longevity Insti-

tute of New York. Dr. Nacht is senior vice president of

Advanced Po/ymer Systems, Redwood City, CA.

32 Cosmetic Dermatology DECEMBER1999

Vitamin K 1o

c((CH3

I I CH'l CH'l~

0CH2CH- t LH2CH2CH2~H]~H,

(2-methyl-3-phytyl-1-4-naphthoquinone)

Fig. 1: Structure of phytonadione (Vitamin K1).

Fig. 2: Structure of retinol.

the background melanin content of the skin~When thisoccurs in an area in which the skin is already thin, theresult can be an increase in the underlying problem, re-gardless of its nature. Thus, the combination of an in-herited tendency to increased melanin in the area, in-creased vessels and actinic damage of the area canproduce the dark circles, No single formulation has beenable to address this combination of factors and certainlyno moisturizer can affect it in any way.

THE FORMULATION

A formulation has been developed consisting of vitaminK1, (phytonadione) (Fig.1), and vitamin A (retinol) (Fig. 2)in a Microsponge@system (Advanced Polymer Systems,Redwood City, CA). Topical Vitamin K1 has been shownin another study to decrease the appearance of darkcircles.

The formulation used in this study consists primarilyof 1% Phytonadione and 0.15% retinol entrapped in a

Fig. 3a: 47-year-old white Fig. 3b: Same patient, 16

female at baseline. weeks later.

polymeric delivery system. The effects of retinoids (vita-min A derivatives) are well known on both the dermisand the epidermis. ln the treatment of photoaging, thereis normalization of epidermal turnover leading to a morecompact stratum corneum, re-establishment of the reteridges and improvement of the full epidermal architec-ture. ln addition, there is repair and increase in dermalvessels to a small degree.6 Vitamin K has been shownin clinical studies to prevent and erase purpura, de-crease pigment, and repair blood vessels in the skin.?Due to the similarities between its chemical structureand that of ubiquinpne, it seems reasonable to assumethat vitamin K1can 'be both an antioxidant and a bleach-ing agent.

By slowly controlling the release of the vitamins intothe skin, the polymeric system reduces the tendency forthe retinol to produce irritation, and thus results in agreater overall penetration of the vitamin over time. Also,there appears to be a benefit in increasing moisturiza-tion in the ocular area due to the presence of the poly-mer itself.

It is important to remember that the polymer remainson the surface of the skin and gradually releases the en-trapped vitamins for penetration through the stratumcorneum, into the epidermis and the dermis; the rate ofrelease from the polymer and, therefore, entry into theskin is determined by the interaction between the activeingredients in the polymer, the re-mainder of the base, and the stra- ......----tum corneum.s

CLINICAL STUDY

Thirty subjects met the criteria forentry into the study. They were ob-tained from the general populationof the Dermatology Center inNashville and from solicitation bynewspaper advertising for individ-uals with dark circles. Subjectscould be male or female, over 18years of age, non-users of Retin-A, glycolic acid and topical vitamin

~TABLE 1

M.L. Elson and S. Nacht

C, must agree to participate in the study for a period ofat least 16 weeks, allow photographs to be obtained,and to undergo no cosmetic procedures of any typeduring the course of the study. Observations were madeafter 2, 4, 8, 12, and 16 weeks of treatment. At thesetimes, the subjects were observed and questioned forpotential side effects and photographs of both eyeswere obtained.

Since no other treatment had previously been shownto be effective for dark circles, the subjects and thebaseline photographs served as their own controls withglobal evaluation by the subjects and comparison of thephotographs at baseline and 16 weeks by the investi-gator to determine the degree of benefit from applica-tion of the cream.

Participants were to apply the cream on moist skin tothe lower and lateral eyelid area at bedtime, using asmall amount, about the size of a grain of rice. No othertreatments or moisturizers were allowed and only cleans-ing with a provided mild cleanser (Cetaphil) and foun-dation were allowed to be used in the morning.

One subject dropped out because he could not keephis scheduled visits and a second developed irritation.This subject was closed patched-tested to the creamand the test was negative at 72 hours, but she devel-oped dryness and irritation when she attempted to usethe cream. Some individuals developed dryness andslight irritation during the initial week of use. However,by instructing the subjects to make certain that theyused a small amount of material and on moist skin, itwas possible for them to continue without irritation be-ing a problem. At the end of the study, two participantswere not certain there was a significant improvementwith the treatment, but the other 26 (93%) rated thecream successful in alleviating their dark circles by di-rect evaluation. Based on the investigators' evaluation ofphotographs obtained at baseline and at 16 weeks, aswell as observation of the patients, the formulàtion wasfound effective in treating dark circles under the eyes.

DARI< CIRCLES REDUCTION - ASSESSMENT FROM PHOTOGRAPHS

pMean Score* % Reduction:t SD

Baseline 14 :t 5.2

2 weeks 11.6 :t 5.3 17

4 weeks 10.4 :t 5.8 26

8 weeks 9.4 :t 4.2 33

12 weeks 7.5 :t 3.2 46

16 weeks 6.2 :t 2.0 56

* mean of total dark circle scores of 11 subjects

<0.02

<0.01

<0.01

<0.01

<0.01

DECEMBER1999 Cosmetic Dermatology 33

Periorbital Hyperpigmenta tion

Fig. 4a: 28-year-old white Fig. 4b: Same patient, 16male at baseline. weeks later.

(Figures 3a-b & 4a-b are representative photographs ofsubjects during the study.)

Two independent expert graders reviewed all the pho-tographs obtained in the study. Some of the pho-tographs were considered inadequate for technical rea-sons. In addition, not all of the subjects completed allthe observations, or they returned at various intermedi-ate times that did not coincide with the stipulated ones.

For these various reasons, 11 subjects were consid-ered evaluable for quantification by expert graders. Foreach one of these subjects, two photographs of the lefteye (front and side view) and two of the right eye wereselected for each observation ~oint.

A 10-point analog scoring scale was used for evalu-ation where "0" was defined as no difference betweenthe color of the skin under theeye and that of the restof the face and "10" was considered to be a point withsevere (maximum imaginable) darkness in the area sur-rounding under the eye.

The photographs were randomly projected onto ascreen and scored separately by the two graders.

These total scores were tabulated, added for eachobservation time, and a mean score was calculated.These are presented in Table 1. Statistical significanceof the reduction at various observation times mean scorevs. the baseline mean score was calculated bya relatedsample t-test. Reduction in darkness mean scores werestatistically significant (p~ 0.05) at each and all observa-tion points.

SUMMARY

ln summary, a topical formulation containing 1% phy-tonadione and 0.15% retinol that utilizes a patented de-livery technology to provide slow gradual release intothe skin provides significant improvement in the ap-pearance of periorbital hyperpigmentation (dark circlesunder the eyes) without any important side-effects.Twenty six out of 28 (93%) of the patients achieved ben-efits as determined by patient self-evaluation and inves-tigator evaluation of the photographs at the beginningand the end of the time period of use of the cream.When photographs from a sub-group of these subjects

34 Cosmetic Dermatology DECEMBER1999

obtained at various intermediate times were evaluatedand quantified by two independent observers, thechanges from baseline were found to be statistically sig-nificantat allobservationtimes. .

Disclosure of Interest: Dr. Elson holds the patent for top-ical Vitamin K, and receives royalties from AdvancedPolymer Systems for topical Vitamin K.

REFERENCES

1. Elson ML. Evaluation and treatment of the aging face. In: ElsonML. Evaluation and Treatment of the Aging Face. New York:Springer-Verlag; 1994:1-8.Rigel OS. Sunscreen: prevention of aging and skin cancer. In: EI-son ML. Evaluation and Treatment of the Aging Face. New York:Springer-Verlag; 1994:9-15.Ryan TJ. The microcirculation of the skin in old age. Gerontal

Clin. 1966;8:327.Pinnell S. Topical vitamin C protects porcine skin from ultravioletradiation-induced damage. Br J Dermatal. 1992; 127[3]:247 -253.Elson ML. Topical phytonadione (vitamin Ki) in the treatment ofactinic and traumatic purpura. Cosmet Dermatal. 1995;8:25-27.Kligman AM, Grove GL, Hirose R, Leyden JL. Topical tretinoin forphotoaged skin. JAm Acad Dermatal. 1986;15:836.

Elson ML. Resurfacing procedures: chemicals and topical ther-apy. ln: Klein AW, ed. Tissue Augmentation in Clinical Practice.

Procedures and Techniques. New York: Marcel Dekker; 1998:307.Eury R, Patel R, Longe K, et al. Microsponge delivery systems(MOS): a topical delivery system with multiple mechanism for trig-gering the release of actives. Cosmetic and Pharmaceutical Ap-

plications of Polymers. New York: Plenum Press; 1991 :169-179.

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@ Copyright. Cosmetic Dermatology, December 1999.