Birch-based Topical Product to Treat Partial-thickness Skin Wounds Approved as a Drug in Europe
Episalvan (Amryt AG; Niefern-Öschelbronn, Germany) is a topical gel containing dry extract of bark from either of two species of birch trees (Betula pendula and B. pubescens, Betulaceae) and/or their hybrids. The birch bark extract is rich in triterpenes, containing about 80% betulin. In 2016, the European Medicines Agency (EMA) approved Episalvan as a prescription drug to treat partial-thickness skin wounds. These are wounds in which the upper layers of the skin (epidermis and upper dermis) have been lost as a result of burns or surgical skin grafting. Episalvan is the only drug approved in Europe to accelerate wound closure in partial-thickness wounds. The purpose of the article was to summarize the development of this drug.
Betulin has two properties important for its therapeutic applications. The first is that it stabilizes water-in-oil emulsions by a mechanism that forms a gel network in oil (an oleogel). Second, the oleogel is more solid at body temperature than at room temperature and is thixotropic, meaning that it liquefies when agitated and thickens at rest. This makes the gel easy to apply as a liquid, after which it solidifies to remain on the skin. Two patents based on these properties were obtained in Germany. Birken GmbH was founded in 2000 to develop pharmaceuticals containing betulin. The company was renamed Birken AG in 2011 and acquired by Amryt AG in 2017.
Betulin and other triterpenes were reported to have anti-inflammatory, antiviral, and tumor-inhibiting activities. Safety and toxicology tests were conducted on dry betulin extract, and the extract was found to have excellent tolerability. A betulin emulsion was developed and incorporated into a commercial cosmetic cream in 2004. A phase II clinical trial was initiated to test the effectiveness of betulin gel on wound healing in patients undergoing skin grafts. Wounds left after removal of healthy skin for grafting were covered with a non-adhesive siliconized dressing. One half of the wound had betulin gel applied and the other half did not. Wound closure was evaluated by the degree of re-epithelialization (regrowth of the skin tissue). Re-epithelialization occurred significantly faster in wounds treated with betulin gel.
Three-phase III trials were conducted in Europe to evaluate the effectiveness of betulin oleogel on wound healing in patients with skin grafts or second-degree burns. In all three trials, wound healing was faster with betulin gel treatment than with dressing alone. Wounds healed 1.8-2.5 days sooner when evaluated by the treating doctor, and 1-2 days sooner when evaluated by blinded doctors examining photographs of the wounds. Skin texture, redness, and pigmentation were significantly better with betulin gel treatment compared to dressing alone after three and 12 months. In October 2014, Birken AG applied to the EMA for approval of betulin gel as a drug with a new active ingredient. In January 2016, the EMA granted approval for Episalvan in 28 European countries.
Several mechanisms of action for betulin were identified during the drug development process. Betulin is involved in all three phases of wound healing. In the inflammatory phase, betulin upregulates inflammation mediators. In the skin cell migration phase, betulin increases cell migration and speeds re-epithelialization. In the skin cell maturation phase, betulin stimulates skin cell differentiation markers to elicit maturation of the skin barrier.
Birchbark extract is also being developed as a prescription medicine for the treatment of epidermolysis bullosa (EB). EB is a rare disease in which the skin is fragile and easily damaged. EB causes painful blisters, wounds, and scarring of the skin. Birchbark extract containing betulin received an orphan drug designation in Europe in 2011 and in the United States in 2014. A phase II trial found that birch bark extract accelerated re-epithelialization in patients with EB, and a phase III trial was in progress at the time of publication of the review.
The author is the inventor of patents for the betulin emulsion and betulin oleogel. He was the director of Birken GmbH and Birken AG from 2000 until April 2016.
Scheffler A. The wound healing properties of betulin from birch bark from bench to bedside. Planta Med. May 2019;85(7):524-527. doi: 10.1055/a-0850-0224.