M.S. Nesterov Head of the Laboratory of Bioanalytical Research, Scientific Center of Biomedical Technologies of the Federal Medical and Biological Agency of Russia (Moscow region, Krasnogorsky district, village Bright mountains, Russia) E-mail: D.V. Khvostov Junior Research Scientist, the Laboratory of Molecular Biology and Bioinformatics, V.M. Gorbatov Federal Research Center for Food Systems, Russian Academy of Sciences (Moscow, Russia) E-mail: R.A. Ageldinov Research Scientist, Laboratory for Bioanalytical Research, Scientific Center of Biomedical Technologies of the Federal Medical and Biological Agency of Russia (Moscow region, Krasnogorsky district, village Bright mountains, Russia) E-mail: D.D. Petrunin Ph.D. (Med.), Scientific Affairs Associate, Russia & CIS, LEO Pharma (Moscow, Russia) E-mail:

For a long time azelaic acid (AZA) have been used for the topical treatment of acne, rosacea and melasma; cumulative clinical data acquired in high-quality randomized clinical trials of azelaic acid referent remedy demonstrates it’s efficacy and good safety profile. In recent time several AZA generic drugs have entered Russian market. In this experimental work, the size factor and zeta-potential (charge factor) of AZA particles in tested samples of the referent product Skinoren® and generics was studied. It was found out that AZA generics have higher parameters of hydrodynamic radius (size fac-tor) and smaller (in module) parameters of zeta-potential than the referent product; this can have a potentially negative impact on stability, shelf life and storage conditions of generics and, in some cases, potentially can affect cutaneous pharmacokinetics and resulting clinical efficacy of the latter.

azelaic acid
referent drug
particle size

  1. Federal'nye klinicheskie rekomendatsii po vedeniju bol'nyh akne / pod red. A.V. Samtsova, E.R. Aravijskoj. Moskva, 2013. 20 s [Federal clinical guidelines for treatment of patients with acne. A.V. Samtsov, E.R. Araviyskaya (eds.). Moscow, 2013; 20 p. (in Russian)].
  2. Hollnick H.P., Zouboulis C.C. Not all acne is acne vulgaris. Dtsch Arztebl Int 2014; 111: 301–312.
  3. Pawin H., Chivot M., Beylot C., et al. Living with acne. A study of adolescents’personal experiences. Dermatology. 2007; 215(4):308–314.
  4. Franzke N., Zimmer L., Schäfer I., Radermacher C., Kresken J., Augustin M. Quality of medical care of patients with acne vulgaris in Germany – nationwide survey of pharmacy clients. J Dtsch Dermatol Ges. 2009; 7: 1060–1063.
  5. Nast A., Dréno B., Bettoli V., et al. European evidence-based (S3) guidelines for the treatment of acne. J Eur Acad Dermatol Venereol. 2012; 26(Suppl 1): 1–29.
  6. Fitton A., Goa K.L. Azelaic acid. A review of its pharmacolog-ical properties and therapeutic efficacy in acne and hyperpig-mentary skin disorders. Drugs. 1991; 41(5):780-798.
  7. Caprilli F., Mercantini R., Nazzaro-Porro M., et al. Studies of the genus Pityrosporum in submerged culture. Mycopatholo-gia et Mycologia Applicata. 1973; 51:171–189.
  8. Nazzaro-Porro M., Passi S. Identification of tyrosinase inhibi-tors in cultures of Pityrosporum. J Invest Dermatol. 1978; 71:205–208.
  9. Nguyen Q.H., Bui T.P. Azelaic acid: pharmacokinetic and pharmacodynamics properties and its therapeutic role in hy-perpigmentary disorders and acne. Int. J. Dermatol. 1995; 34(2):75–84.
  10. Nazzaro-Porro M., Passi S., Picardo M., et al. Beneficial ef-fect of 15% azelaic acid cream on acne vulgaris. Br. J. Derma-tol. 1983; 109:45–48.
  11. Mastrofrancesco A., Ottaviani M., Aspite N., Cardinali G., Iz-zo E., et al. Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARγ activation. Exp. Dermatol. 2010; 19: 813–820.
  12. Briganti S., Flori E., Mastrofrancesco A., Kovacs D., Camera E., et al. Azelaic acid reduced senescencelike phenotype in photo-irradiated human dermal fibroblasts: possible implica-tion of PPARγ. Exp. Dermatol. 2013; 22: 41–47.
  13. Akamatsu H., Komura J., Asada Y., Miyachi Y., Niwa Y. In-hibitory effect of azelaic acid on neutrophil functions: a possi-ble cause for its efficacy in treating pathogenetically unrelated diseases. Arch. Dermatol. Res 1991; 283: 162–166.
  14. Passi S., Picardo M., De Luca C., Breathnach A.S., Nazzaro-Porro M. Scavenging activity of azelaic acid on hydroxyl
  15. radicals ‘in vitro’. Free Radic. Res. Commun. 1991; 11:
  16. 329–338.
  17. Leeming J., Holland K., Bojar R. The in vitro antimicrobial ef-fect of azelaic acid. Br. J. Dermatol. 1986; 115:551–556.
  18. King K., Leeming J., Holland K., Cunliffe W. The effect of azelaic acid on cutaneous microflora in vivo and in vitro. J. In-vest. Dermatol 1985; 84: 438.
  19. Ozkan M., Durmaz G., Sabuncu I., Saracoglu N., Akgun Y., Urer S. Clinical efficacy of topical clindamycin phosphate and azelaic acid on acne vulgaris and emergence of resistant coagu-lase-negative Staphylococci. Turk. J. Med. Sci. 2000; 30: 483–487.
  20. Maple P.A., Hamilton-Miller J.M., Brumfitt W. Comparison of the in-vitro activities of the topical antimicrobials azelaic acid, nitrofurazone, silver sulphadiazine and mupirocin against methicillin-resistant Staphylococcus aureus. J. Antimicrob. Chemother. 1992; 29:661–668.
  21. Bladon P.T., Burke B.M., Cunliffe W.J., Forster R.A., Holland K.T., King K. Topical azelaic acid and the treatment of acne: a clinical and laboratory comparison with oral tetracycline. Br. J. Dermatol. 1986; 114: 493–499.
  22. Cunliffe W.J., Holland K.T. Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne. Acta Derm. Venereol. Suppl. (Stockh) 1989; 143: 31–34.
  23. Farag A., Ananieva L. Acne vulgaris: ultrastructure changes after treatment with 20% azelaic acid. J. Dermatolog. Treat. 1995; 6: 151–154.
  24. Bojar R.A., Cutcliffe A.G., Graupe K., Cunliffe W.J., Holland K.T. Follicular concentrations of azelaic acid after a single top-ical application. Br. J. Dermatol. 1993; 129: 399–402.
  25. Bojar R.A., Cunliffe W.J., Holland K.T. Disruption of the transmembrane pH gradient – a possible mechanism for the antibacterial action of azelaic acid in Propionibacterium acnes and Staphylococcus epidermidis. J. Antimicrob. Chemother. 1994; 34: 321–330.
  26. Bojar R.A., Holland K.T., Cunliffe W.J. The invitro antimicro-bial effects of azelaic acid upon Propionibacterium acnes strain P37. J. Antimicrob Chemother. 1991; 28: 843–853.
  27. Bojar R.A., Cutcliffe A.G., Graupe K., Cunliffe W.J., Holland K.T. Azelaic acid: a review of its antimicrobial properties. Rec Contemp Pharmacother. 1993; 4: 403–414.
  28. Gollnick H., Mayer-da-Silva A., Orfanos C.E. Effects of azelaic acid on filaggrin, other cytokeratins and on the ultra-structure of human keratinocytes in vivo. J. Invest. Dermatol. 1987; 89:452.
  29. Barbareschi M., Hendricks I., Angius A., Cattaneo M., Monti M. The anticomedonic activity of azelaic acid investigated by means of scanning electron microscopy on horny layer biopsy. J. Dermatolog. Treat. 1991; 2: 55–57.
  30. Geier G., Hauschild T., Bauer R., Kreysel H. Der Einfluss von Azelainsaure auf das Wachstum von Melanomzellkulturen im Vergleich zu Fibroblastenkulturen. Hautarzt. 1986; 37: 146–148.
  31. Zaleski-Larsen L.A., Fabi S.G., McGraw T., Taylor M. Acne Scar Treatment: A Multimodality Approach Tailored to Scar Type. Dermatol Surg. 2016; 42(2): 139–149.
  32. Galhaup I. Azelaic acid: mode of action at cellular and subcel-lular levels. Acta Derm. Venereol. [Suppl.] (Stockh). 1989; 143: 75–82.
  33. Passi S., Picardo M., Mingrone G., et al. Azelaic acid: bio-chemistry and metabolism. Acta Derm. Venereol. [Suppl.] (Stockh). 1989; 143: 8–13.
  34. Breathnach A., Nazzaro-Porro M., Passi S., Zina G. Azelaic acid therapy in disorders of pigmentation. Clinics Dermatol. 1989; 7: 106–119.
  35. Iraji F., Sadeghinia A., Shahmoradi Z., Siadat A.H., Jooya A. Efficacy of topical azelaic acid gel in the treatment of mild-moderate acne vulgaris. Indian J. Dermatol. Venereol. Leprol. 2007; 73: 94–96.
  36. Angius A.G., Barbareschi M., Cattaneo M., Monti M., Caputo R. Evaluation of the anticomedo effect of azelaic acid using the technique of horny layer biopsy and scanning electron micros-copy (in Italian). G. Ital. Dermatol. Venereol. 1990; 125: XXXIII–XXXVI.
  37. Katsambas A., Graupe K., Stratigos J. Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Compari-son with vehicle and topical tretinoin. Acta Derm. Venereol. Suppl. (Stockh). 1989; 143: 35–39.
  38. Krishna G., Kligman A.M., editors. Acne and Rosacea, 3rd ed. Berlin, Germany: Springer-Verlag; 2000. 756 p.
  39. Krishna S., Kim C., Kim J. Innate immunity in the pathogene-sis of acne vulgaris. In: Shalita A.R., Del Rosso J.Q., Webster G.F., editors. Acne Vulgaris. London: Informa Healthcare; 2011: 12–27.
  40. Stamatiadis D., Bulteau-Portois M.C., Mowszowicz I. Inhibi-tion of 5a-reductase activity in human skin by zinc and azelaic acid. Br. J. Dermatol. 1988; 119: 627–632.
  41. Limburg J., Zettergren J., Swanson J., et al. Topical effect of 6-Methylene progesterone and azelaic acid on hamster ear se-baceous gland lipogenesis and morphology. J. Invest. Derma-tol. 1989; 92: 472.
  42. Rach P., Topert M. Pharmacological investigation of azelaic acid. J. Invest. Dermatol. 1986; 86: 327.
  43. Gollnick H.P., Krautheim A. Topical treatment in acne: current status and future aspects. Dermatology. 2003; 206: 29–36.
  44. Passi S., Nazzaro-Porro M., Picardo M., et al. Metabolism of straight saturated medium chain length C9 to C12 dicarboxylic acids. J. Lipid Res. 1983; 24: 1140–1147.
  45. Del Rosso J.Q., Lehman P.A., Raney S.G. Impact of order of application of moisturizers on percutaneous absorption kinet-ics: evaluation of sequential application of moisturizer lotions and azelaic acid gel 15% using a human skin model. Cutis. 2009; 83: 119–124.
  46. Mingrone G., Greco A., Nazzaro-Porro M., Passi S. Toxicity of azelaic acid. Drugs Exp. Clin. Res. 1983; 9:447–455.
  47. Topert M., Rach P., Siegmund F. Pharmacology and toxicolo-gy of azelaic acid. Acta Derm. Venereol. [Suppl.] (Stockh). 1989; 143: 14–19.
  48. Bertuzzi A., Gandolfi A., Salinari S., et al. Pharmacokinetic analysis of azelaic acid disodium salt. A proposed substrate for total parenteral nutrition. Clin. Pharmacokinet. 1991; 20: 411–419.
  49. Willshaw H.E., Rubinstein K. Azelaic acid in the treatment of ocular and adnexal malignant melanoma. Br. J. Ophthalmol. 1983; 67: 54–57.
  50. Gavicchini S., Gaputo R. Long-term treatment of acne with 20% azelaic cream. Acta Derm. Venereol. [Suppl.] (Stockh). 1989; 143: 40–44.
  51. Verallo-Rowell V.M., Verallo V., Graupe K., et al. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm. Venereol. [Suppl.] (Stockh). 1989; 143: 58–61.
  52. Graupe K., Cunliffe W.J., Gollnick H.P., Zaumseil R.P. Effi-cacy and safety of topical azelaic acid (20 percent cream): an overview of results from European clinical trials and experi-mental reports. Cutis. 1996; 57: 20–35.
  53. Ortonne J.P., Lacour J.P. Assessment of the phototoxicity of azelaic acid using the modified method of Kaidbey and Klig-man. Nouv. Dermatol. 1992; 11: 490–495.
  54. Ferguson J., Johnson B.E. Retinoid associated phototoxicity and photosensitivity. Pharmacol. Ther. 1989; 40: 123–135.
  55. Onoue S., Seto Y., Gandy G., Yamada S. Drug induced photo-toxicity; an early in vitro identification of phototoxic potential of new drug entities in drug discovery and development. Curr. Drug Saf. 2009; 4: 123–136.
  56. Thielitz A., Lux A., Wiede A., Kropf S., Papakonstantinou E., Gollnick H. A randomized investigator-blind parallel-group study to assess efficacy and safety of azelaic acid 15% gel vs. adapalene 0.1% gel in the treatment and maintenance treatment of female adult acne. J. Eur. Acad. Dermatol. Venereol. 2015; 29(4): 789–796.
  57. Gollnick H.P., Graupe K., Zaumseil R.P. Azelaic acid 15% gel in the treatment of acne vulgaris. Combined results of two double-blind clinical comparative studies. J. Dtsch. Dermatol. Ges. 2004; 2(10): 841–847.
  58. Webster G. Combination azelaic acid therapy for acne vulgaris. J. Am. Acad. Dermatol. 2000; 43: S47–50.
  59. Hjorth N., Graupe K. Azelaic acid for the treatment of acne: a clinical comparison with oral tetracycline. Acta Derm. Venere-ol [Suppl.] (Stockh). 1989; 143: 45–48.
  60. Gollnick H., Graupe K. Azelaic acid for the treatment of acne: comparative trials. J. Dermatol. Treat. 1989; 1: 27–30.
  61. Batyrshina S.V., Gordeeva A.M., Bogdanova M.A., Bulga-kova D.R. Effektivnost'geljaskinorenv naruzhnoj tera-pii bol'nyh ugrevoj bolez'ju i rozatsea. Vestnik derma-tologii i venerologii. 2004; 6: 3–6 [Batyrshina S.V., Gor-deeva A.M., Bogdanova M.A., Bulgakova D.R. Skinoren gel for topical treatment of acne vulgaris and rosacea. Vestnik Dermatologii i Venerologii. 2004; 6: 3–6 (in Russian)].
  62. Pazoki-Toroudi H., Nilforoushzadeh M.A., Ajami M., Jaffary F., Aboutaleb N., Nassiri-Kashani M., Firooz A. Combination of azelaic acid 5% and clindamycin 2% for the treatment of ac-ne vulgaris. Cutan Ocul. Toxicol. 2011 Dec; 30(4): 286–291.
  63. Pazoki-Toroudi H., Nassiri-Kashani M., Tabatabaie H., Aja-mi M., Habibey R., Shizarpour M., Babakoohi S., Rahshenas M., Firooz A. Combination of azelaic acid 5% and erythromy-cin 2% in the treatment of acne vulgaris. J. Dermatolog. Treat. 2010 May; 21(3): 212–216.
  64. Panteleeva G.A. Gel' skinoren v terapii akne. Vestnik dermatologii i venerologii. 2005; 1: 62–63 [Panteleeva G.A. Skinorengelin therapy of acne. Vestnik Dermatologii i Venerologii. 2005; 1: 62–63 (in Russian)].
  65. Perlamutrov Ju.N., Ol'hovskaja K.B. Skinoren gel' v te-rapii i profilaktike akne. Klinicheskaja dermatologija i venerologija. 2007; 4: 40–43 [Perlamutrov Ju.N., Olkhovskaya K.B. Skinorengelin therapy and prophylaxis of acne. Klinicheskaya Dermatologiya i Venerologiya. 2007; 4: 40–43 (in Russian)].
  66. Jutskovskaja Ja.A., Markelova E.V., Taran M.G., Koval'chuk E.V., Rahmanova S.N. Azelainovaja kislota v naruzhnom lechenii ugrevoj bolezni legkoj i srednej stepenej tjazhe-sti. Klinicheskaja dermatologija i venerologija. 2011; 5: 60–69 [Iutskovskaia Ia.A., Markelova E.V., Taran M.G., Ko-val'chuk E.V., Rakhmanova S.N. The use of azelainic acid in the external treatment of mild and moderately severe acne dis-ease. Klinicheskaya Dermatologiya i Venerologiya 2011; 5:60–69 (in Russian)].
  67. Matushevskaja E.V., Svirschevskaja E.V. Azelainovaja kislo-ta v praktike vracha-dermatologa i kosmetologa. Kliniche-skaja dermatologija i venerologija. 2014; 5: 11–17 [Matu-shevskaia E.V., Svirshchevskaia E.V. Azelaicacid in dermato-logical and cosmetological practice. KlinicheskayaDerma-tologiya i Venerologiya. 2014; 5: 11–17 (inRussian)].
  68. Statsenko A.V., Gorbunov Ju.G., Hajrutdinov V.R., She-stopalov N.E., Antonova O.V. Opyt primenenija azelai-novoj kisloty v terapii bol'nyh akne. Vestnik dermato-logii i venerologii. 2014; 5: 100–105 [Statsenco A.V., Gorbunov U.G., Khairutdinov V.R., Shestopalov N.E., An-tonova O.V. Experience use of azelaicacid in patients with ac-ne. Vestnik Dermatologii i Venerologii. 2014; 5: 100–105 (in Russian)].
  69. Samtsov A.V. Novoe v izuchenii akne u zhenschin. Vestnik dermatologii i venerologii 2014; (1): 64–68 [Samtsov A.V. New aspects in studies of acne in women. Vestnik Der-matologii i Venerologii. 2014; (1): 64-68 (in Russian)].
  70. Monahov K.N., Dombrovskaja D.K. Kompleksnaja naruzhnaja terapija vul'garnyh ugrej. Vestnik dermatologii i vene-rologii. 2012; 3: 104–10 [Monakhov K.N., Dombrovskaya D.K. Comprensive external therapy of acne vulgaris. Vestnik Dermatologii i Venerologii. 2012; 3: 104–110 (in Russian)].
  71. Kathanova O.A., Kathanov A.M. Akne s pozitsii dermato-loga i kosmetologa. Vestnik dermatologii i venerologii 2014; 4: 75–82 [Katkhanova O.A., Katkhanov M.A. Acne from the point of view of dermatologists and cosmetologists. Vestnik Dermatologii i Venerologii. 2014; 4: 75–82 (in Russian)].
  72. Matushevskaja E.V., Svirshevskaja E.V. Effektivnost' i bezopasnost' mikronizirovannyh lekarstvennyh prepa-ratov i ih primenenie v dermatologicheskoj praktike. Klinicheskaja dermatologija i venerologija. 2015; 14(5): 4–10 [Matushevskaya E.V., Svirshevskaya E.V. Efficacy and safety of micronized medicines and their use in dermatological practice. Klinicheskaya Dermatologiya i Venerologiya. 2015; 14(5): 4–10].
  73. Bulbake U., Doppalapudi S., Kommineni N., Khan W. Lipo-somal Formulations in Clinical Use: An Updated Review. Pharmaceutics. 2017; 9(2). DOI: 10.3390/pharmaceutics9020012.