Seborrheic Dermatitis

TU-2100 - A Novel Topical Sebostatic Preparation
Tamarkin Pharmaceutical Innovation (2 February 2000)

Author: Dov Tamarkin, Ph.D.

ABSTRACT

There is currently no topical therapy to influence the production of
sebum and thus, the treatment of oily skin and seborrhea still
remains an unmet need. TU-2100 is a novel pro-drug, composed of
azelaic acid and ethyl salicylate, which was designed to penetrate
the pilosebaceous unit and control sebum production. In effort to
test the safety and efficacy of this agent, TU-2100 10% lotion was
applied twice daily for 8 weeks to the face of ten women with oily
skin. Sebum excretion rates declined by 30-44%, reaching normal

levels within 8 weeks of treatment in all study volunteers. Notably,
neither skin irritation, nor systemic adverse reactions were noted
throughout the study.

Hence, TU-2100 is an effective sebum control agent, making it a
useful treatment for oily skin and seborrhea. Moreover, due to its
combined sebostatic and comedolytic properties, TU-2100 is also
effective treatment for acne, as revealed in our subsequent trials.

INTRODUCTION

The biology of the pilosebaceous unit has attracted the attention of
numerous investigators on account of its involvement in important
skin functions, including hair growth and sebum excretion.
Malfunctioning of the pilosebaceous unit is the cause of common skin
disorders, such as acne, seborrhea, dandruff, androgenic alopecia and
hirsutism. Androgen metabolism plays an important role in the control
of both sebum excretion rate (SER) and keratinization patterns in the
pilosebaceous unit. The enzyme 5-a -testosterone reductase is
responsible for the conversion of testosterone to dihydrotestosterone
(DHT), and DHT is known to modulate both keratin formation and sebum
production.1,2,3 Reducing sebum excretion is not an easy task. In his
recent review, titled "Therapy For Acne Vulgaris", J. Leyden
stated: "No topical therapies influence the production of sebum".4
Indeed, clinical studies with various topical anti-acne medications,
including tretinoin and other retinoids, benzoyl peroxide and azelaic
acid did not reveal any significant reduction of SER in acne and
seborrhea - prone subjects.5,6,7,8 Topical application of the
antiandrogen, inocoterone acetate did not reduce sebum excretion
either.9 Other androgen antagonists, spironolactone and17-a -
propylmesterolone, produced a significant reduction in SER, which
occurred 12 weeks after the initiation of topical treatment.10,11
Interestingly, oral 13-cis-retinoic acid (accutan) and oral 9-cis-
retinoic acid profoundly suppressed sebum excretion, with a long-
lasting residual effect,12,13,14 whereas oral tretinoin did not.15

TU-2100 (Nonanedioic acid, bis[(2-(ethoxycarbonyl)phenyl] ester) is a
novel dual-action pro-drug, composed of azelaic acid and ethyl
salicylate. Both pro-drug components possess anti-acne properties,
however, due to their hydrophilic character, they barely penetrate
the skin and thus, their therapeutic benefits are limited. By
contrast, TU-2100 is highly lipophylic and readily penetrates the
follicle. Non-specific esterases in the skin hydrolyze this pro-drug
and liberate its components to exert their effects inside their
target site of action. Consequently, azelaic acid may then act via
its 5-a -reductase inhibiting property (hitherto revealed only in
vitro)16,17 and exert its keratolytic and antibacterial effects.17
Salicylic acid contributes to the therapeutic effect by its
keratolytic and anti-inflammatory properties. In vivo studies, using
the rabbit ear model, revealed that this agent was comedolytic,
without the skin irritation which is typical to other potent anti-
acne medications, such as Retin A®.18 In vitro studies have
demonstrated that TU-2100 inhibits keratinocyte proliferation, thus
supporting the in vivo results. The above-mentioned observations led
us to initiate human studies, aimed to assess the safety of topically
applied TU-2100 and to evaluate its effect on sebum excretion.

MATERIALS AND METHODS

The present exploratory human study was carried out at S.K.I.N.,
Incorporated, Conshohocken, Pennsylvania and the principal
investigator was Dr. Albert M Kligman. Ten adult female volunteers,
mean age of 33 years (range 25-46), with oily facial skin were
enrolled in this exploratory study. They were free of dermatoses and
were not receiving any prescribed drugs. After signing an Informed
Consent form, they were instructed to apply TU-2100 10% (dissolved in
ethanol-PEG 400, 9:1) twice daily to the forehead and cheeks. The
volume applied was adjusted to an approximate amount 2 mg/cm2. They
were also told not to apply the test lotion during a 24 hr-period
preceding scheduled clinic visits on the 4th and 8th week of the
study. Safety evaluations were based on detection of potential skin
irritation, as well as clinical chemistry and hematological
parameters at study termination. Sebum excretion levels were assessed
on the central forehead and nasolabial region of the cheek (sebum-
test sites) at baseline and on the 4th and 8th week of the study,
using the Sebutape® technique as previously described.19

RESULTS AND CONCLUSION

No clinically significant deviations from the normal values of serum
chemistry and hematology were observed after eight weeks of
treatment. There was no skin irritation. Neither changes in skin
infrastructure, nor skin dryness, redness or peeling were noted
during the 8-week period.

In all volunteers, baseline sebum excretion levels on the forehead
were higher than those detected on the nasolabial area of the cheek.
Baseline SER measurements indicated oily to very-oily forehead skin
and oily skin at the nasolabial region of the cheek (% Areas covered
by spots = 8.4 ± 1.1 and 6.2 ± 0.4, respectively). Mean sebum
excretion rates after 4 weeks of repeated TU-2100 10% application,
declined 33% (forehead) and 26% (cheek) and reached normal values in
all the participants. Following 8 weeks of treatment, SER was 56% and
70% of the baseline values at the forehead and cheek, respectively
(Figure 1). These decreases in sebum excretion rate were
statistically significant at a 95% confidence level and with p values
of <0.01 in both the forehead and cheek (ANOVA, Dunnett Multiple
Comparison).

In light of the results of this exploratory study, the following
conclusions were drawn: 1) TU-2100 can normalize sebum excretion,
making it useful in the treatment of oily skin and seborrhea. 2)
Based on the effect of TU-2100 on sebum excretion and in light of its
comedolytic and anti-inflammatory properties, it is reasonable to
conclude that TU-2100 may be effective in the treatment of acne
vulgaris.

Further controlled studies are underway, to establish the therapeutic
effect of TU-2100 in seborrhea, acne, psoriasis and possibly other
disorders of the pilosebaceous unit.

Figure 1. The Influence of TU-2100 10% Topical Administration on
Sebum Excretion Rate, Expressed as % Area Occupied by Sebum Spots.
Each line represents an individual study volunteer. (Skin Oiliness
Reference: Low: 4%>; Normal: 4-6.5%; Oily: 6.5-9%; Very Oily: >9%).20

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Data from CuDerm Corp., Dallas, TX; Each 1% Area Occupied by Sebum
Spots represents Sebum Excretion Rate of 9.5 nl/cm2/hr.
Author contact details

Dov Tamarkin, Ph.D.

Tamarkin Pharmaceutical Innovation, Ltd.

Tamar-Science Park, P. O. Box 2463 Rehovot 76123, Israel

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