The Wound Healing Properties of Betulin from Birch Bark from Bench to Bedside

Abstract

With central European approval in January 2016 for a betulin-oleogel (Episalvan), used to accelerate wound closure in partial thickness wounds, the herbal active ingredient triterpene dry extract (betulin), from birch bark, was introduced into therapy for the first time. Clinical evidence of accelerated wound healing was provided in a new study design by means of intraindividual comparison of split-thickness skin graft donor wounds and burn wounds. Clinical results of a phase II study evidencing accelerated wound healing in the rare disease epidermolysis bullosa are also available, and a pivotal multi-centre phase III study is currently being conducted. The mode of action affects all three phases of wound healing (inflammation, migration, and differentiation), and it has been possible, in some cases, to shed light on this down to the molecular level. After temporary stimulation of the inflammatory phase, the keratinocytes migrate more rapidly to the wound closure and, finally, epidermal differentiation is stimulated. With this project, we have shown that scientifically founded new developments in phytotherapy are possible in Europe. The active ingredient is new and its indication is for the first time clearly proven in studies. Betulin-oleogel is the first drug of its indication and is patented until 2030. In addition, it is the first phytotherapeutic agent in surgery, and thus opens up a new therapeutic area for phytotherapy. The birch bark contains about 22% betulin in its cork tissue, meaning that the active ingredient is sustainably available from Northern Europeʼs wood-processing industry on a scale of several 100,000 t/a.

Key words

wound healing - split-thickness skin graft - burn wounds - Betulaceae - Betula pendula - Betula pubescens - betulin

• References

• 1 Lowitz JT. Über eine neue, fast benzoeartige Substanz der Birken. Chemische Annalen 1788; 2: 312-316
• 2 Daniels R, Laszczyk MN. Betulin für tensidfreie Emulsionen. Pharm Ztg 2008; 153: 862-863
• 3 Grysko M, Daniels R. Evaluation of the mechanism of gelation of an oleogel based on a triterpene extract from the outer bark of birch. Pharmazie 2013; 68: 572-577
• 4 Scheffler A. Emulsion enthaltend einen Pflanzenextrakt, Verfahren zur Herstellung der Emulsion sowie zur Gewinnung des Pflanzenextraktes. Patent WO/2001/072315, 2001
• 5 Scheffler A. Triterpenhaltiger Oleogelbildner, triterpenhaltiges Oleogel und Verfahren zur Herstellung eines triterpenhaltigen Oleogels. Patent WO/2005/123037, 2005
• 6 Laszczyk M, Jäger S, Simon-Haarhaus B, Scheffler A, Schempp CM. Physical, chemical and pharmacological characterization of a new oleogel-forming triterpene extract from the outer bark of birch (betulae cortex). Planta Med 2006; 72: 1389-1395
• 7 Pisha E, Chai H, Lee IS, Chagwedera TE, Farnsworth NR, Cordell GA, Beecher CW, Fong HH, Kinghorn AD, Brown DM. et al. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1995; 1: 1046-1051 doi:10.1038/nm1095-1046
• 8 Laszczyk MN. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med 2009; 75: 1549-1560
• 9 Hertrampf A, Gründemann C, Jäger S, Laszczyk M, Giesemann T, Huber R. In vitro cytotoxicity of cyclodextrin-bonded birch bark extract. Planta Med 2012; 78: 881-889
• 10 Huyke C, Reuter J, Rödig M, Kersten A, Laszczyk M, Scheffler A, Nashan D, Schempp C. Treatment of actinic keratoses with a novel betulin-based oleogel. A prospective, randomized, comparative pilot study. J Dtsch Dermatol Ges 2009; 7: 128-133
• 11 Jäger S, Zahn T. Das neue Wund-Arzneimittel Episalvan^®: Galenik und Studiendesign. Pharmakon 2016; 4: 349-355
• 12 Metelmann HR, Brandner JM, Schumann H, Bross F, Fimmers R, Böttger K, Scheffler A, Podmelle F. Accelerated reepithelialization by triterpenes: proof of concept in the healing of surgical skin lesions. Skin Pharmacol Physiol 2015; 28: 1-11
• 13 Rennekampff HO, Fimmers R, Metelmann HR, Schumann H, Tenenhaus M. Reliability of photographic analysis of wound epithelialization assessed in human skin graft donor sites and epidermolysis bullosa wounds. Trials 2015; 16: 235
• 14 Barret JP, Podmelle F, Lipový B, Rennekampff HO, Schumann H, Schwieger-Briel A, Zahn TR, Metelmann HR. BSH-12 and BSG-12 study groups. Accelerated re-epithelialization of partial-thickness skin wounds by a topical betulin gel: Results of a randomized phase III clinical trials program. Burns 2017; 43: 1284-1294 doi:10.1016/j.burns.2017.03.005
• 15 Scheffler A. Entwicklung des neuen Phytopharmakons Episalvan (Betulin) zur Wundheilung. Z Phytother 2017; 38: 100-106
• 16 Amryt Pharma. Regulatory news. Available at: http://www.amrytpharma.com/investors/regulatory-news/ Accessed March 4, 2019
• 17 Schwieger-Briel A, Kiritsi D, Schempp C, Has C, Schumann H. Betulin- based Oleogel to improve wound healing in dystrophic Epidermolysis Bullosa: a prospective controlled proof-of-concept study. Dermatol Res Pract 2017; 2017: 5068969
• 18 Ebeling S, Naumann K, Pollok S, Wardecki T, Vidal-Y-Sy S, Nascimento JM, Boerries M, Schmidt G, Brandner JM, Merfort I. From a traditional medicinal plant to a rational drug: understanding the clinically proven wound healing efficacy of birch bark extract. PLoS One 2014; 9: e86147 doi:10.1371/journal.pone.0086147
• 19 Woelfle U, Laszczyk MN, Kraus M, Leuner K, Kersten A, Simon-Haarhaus B, Scheffler A, Martin SF, Müller WE, Nashan D, Schempp CM. Triterpenes promote keratinocyte differentiation in vitro, ex vivo and in vivo: A role for the transient receptor potential canonical (subtype) 6. J Invest Dermatol 2010; 130: 113-123