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 4^th and 8^th 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 4^th and 8^th 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 ; Normal: 4-6.5%; Oily: 6.5-9%; Very Oily:>9%).²⁰

REFERENCES

1. Ebling FJ. Hair follicles and associated glands as androgen targets. Clin Endocrinol Metab 1986; 15: 319-339.
2. Chen W, Zouboulis CC, Orfanos CE. The 5 alpha-reductase system and its inhibitors, recent development and its perspective in treating androgen-dependent skin disorders. Dermatology 1996; 193: 177-184.
3. Randall VA. Role of 5 alpha-reductase in health and disease. Baillieres Clin Endocrinol Metab 1994; 8: 405-431.
4. Cunliffe WJ, Macdonad-Hull S. Lack of effect of topical retinoic acid on sebum excretion rate in acne. Lancet 1998; 2(8609): 503.
5. Leyden JJ. Therapy for acne vulgaris. New Eng J Med 1997; 1156-1162.
6. Goldstein JA, Pochi PE. Failure of benzoyl peroxide to decrease sebaceous gland secretion in acne. Dermatologica 1981; 162: 287-291.
7. Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne. Acta Derm Venereol suppl (Stockh) 1989; 143: 31-34.
8. Mayer-Da-Silva A, Gollnick H, Detmar M, Gassmuller J, Parry A, Muller R, Orfanos CE. Effects of azelaic acid on sebaceous gland, sebum excretion rate and keratinization pattern in human skin. An in vivo and in vitro study. Acta Derm Venereol suppl (Stockh) 1989; 143: 20-30.
9. Lookingbill DP, Abrams BB, Ellis CN, Jegasothy BV, Lucky AW, Ortiz-Ferrer LC, Savin RC, Shupack JL, Stiller MJ, Zone JJ, et al. Inocoterone and acne. The effect of a topical antiandrogen: results of a multicenter clinical trial. Arch Dermatol 1992; 128: 1197-1200.
10. Villares JC, Carlini EA. Sebum secretion in idiopathic Parkinson's disease: effect of anticholinergic and dopaminergic drugs. Acta Neurol Scand 1989; 80: 57-63.
11. Schmidt JB, Spona J. An effective topical antiandrogen - 17 alpha-propylmesterolone in acne. Hautarzt 1987; 38: 470-473.
12. Orfanos CE, Zouboulis CC. Oral retinoids in the treatment of seborrhea and acne. Dermatology 1998; 196(1): 140-147
13. Hughes BR, Cunliffe WJ. A prospective study of the effect of isotretinoin on the follicular reservoir and sustainable sebum excretion rate in patients with acne. Arch Dermatol 1994; 130: 315-318.
14. Ott F, Bollag W, Geiger JM. Oral 9-cis-retinoic acid versus 13-cis-retinoic acid in acne therapy. Dermatology 1996; 193: 124-126.
15. Hommel L, Geiger JM, Harms M, Saurat JH. Sebum excretion rate in subjects treated with oral all-trans-retinoic acid. Dermatology 1996; 193: 127-130.
16. Stamatiadis D, Bulteau-Porotois MC, Mowszowicz I. Inhibition of 5-a -reductase in human skin by zinc and azelaic acid. Br J Dermatol 1988; 119: 627-632.
17. Passi S, Picardo M, De Luca C, Nazzaro-Porro M. Mechanism of action of azelaic acid in the treatment of acne. G Ital Dermatol Venereol 1989; 124: 455-463.
18. Kligman AM. Unpublished results.
19. Pagnoni A, Kligman AM, Gammal S, Popp C, Stoudemayer T. An improved procedure for quantitative analysis of sebum production using Sebutape^®. J Soc Cosmet Chem 1994; 45: 221-225.
20. 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

Tel: +972 8 9316 355; Fax: +972 8 9316 360; E-mail: tdov@inter.net.il

To make any comments on this article, or to ask a question of the author, please contact the publisher. If you would like to submit an article, please contact the editors.

The opinions expressed in the articles published in this section do not necessarily reflect those of Pharmalicensing or UTEK Corporation. No actions including proposals to or agreements with other companies should be taken by any reader without obtaining specific business or legal advice. Neither the publisher nor the authors accept any liability for any actions or activities undertaken by any reader or other third party as a consequence of these articles or for any errors or omissions therein.