Birch bark extract

Identification

Summary

Birch bark extract is a herbal medicinal product used to treat partial thickness wounds.

Brand Names

Filsuvez

Generic Name

Birch bark extract

DrugBank Accession Number

DB16536

Background

Birch bark extract is rich in triterpenoids with beneficial biological and pharmacological activities. Some of the compounds identified in it include betulin, lupeol, betulinic acid, oleanolic acid, and erythrodiol.³ Birch bark extract is obtained from the white part of the birch tree bark, and the main species of trees used for production are Betula pendula Roth (silver birch) and Betula pubescens Ehrh. (white birch), although hybrids of both species are used as well.⁷ Two oleogel formulations of birch bark extract (Oleogel-S10, 10% of triterpene dry extract in sunflower oil) have been approved by the European Medicines Agency.^5,6 Filsuvez, one of these two formulations, is approved for the treatment of partial thickness wounds in patients with epidermolysis bullosa (EB), a rare group of hereditary disorders of the skin, mucous membranes, and internal epithelial linings characterized by extreme skin fragility and blister development.⁸ Filsuvez was subsequently approved for the same indication by the US FDA in December 2023.¹⁰

The EMA marketing authorization for Episalvan⁶ was withdrawn by the manufacturer in 2022.

Type

Small Molecule

Groups

Approved, Experimental

Synonyms

• Betula pendula/pubescens bark
• Betulae cortex extract
• Oleogel-S10

External IDs

• 281-660-9

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Pharmacology

Indication

Filsuvez, a preparation of birch bark extract, is indicated for the treatment of partial thickness wounds associated with dystrophic and junctional epidermolysis bullosa (EB) in patients 6 months and older.^5,9

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Partial thickness wounds		••••••••••••			•••
Treatment of	Partial thickness wounds		••••••••••••			•••
Used in combination to treat	Partial thickness wounds	Combination Product in combination with: Betulinic Acid (DB12480)	••••••••••••	•••••		•••

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Contraindications & Blackbox Warnings

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Pharmacodynamics

Birch bark extract and its main component, betulin, promote wound healing and closure by activating pathways involved in keratinocyte differentiation and migration. Compared to a blinded control gel consisting of refined sunflower oil, beeswax, yellow wax and carnauba wax, Filsuvez (Oleogel-S10, a birch bark extract gel) promotes wound closure in patients with epidermolysis bullosa (EB). This effect was more noticeable in patients with recessive dystrophic EB than in patients with junctional EB (JEB) or dominant dystrophic EB (DDEB). Clinical data supporting the use of Filsuvez in patients with JEB or DDEB is insufficient; therefore, their condition should be evaluated regularly to assess the benefit of continued treatment.⁵ Birch bark extract may cause hypersensitivity, and theoretically, an increased risk of skin malignancies associated with the use of Filsuvez cannot be ruled out.⁵ Although birch bark extract gel is sterile, wound infection may occur during wound healing.⁵

Mechanism of action

Birch bark extract promotes wound healing; however, the specific mechanism of action has not been fully elucidated.⁵ In vitro studies in primary human keratinocytes and fibroblasts and ex vivo studies in porcine skin have shown that the dry extract from birch bark and its component betulin modulate inflammatory mediators. Specifically, pro-inflammatory cytokines such as cyclooxygenase 2 (COX-2), interleukin 6 (IL-6) and interleukin 8 (IL-8) are upregulated at both RNA and protein levels.^1,4,7 The anti-inflammatory activity of other birch bark extract components such as oleanolic acid, erythrodiol, betulinic acid, and lupeol has also been reported.¹

Birch bark extract also plays a role in the formation of new skin barriers by promoting cellular proliferation, migration, adhesion, deposition of matrix, and keratinocyte differentiation.⁷ The dry extract from birch bark and its components betulin, lupeol, and erythrodiol promote keratinocyte migration¹. In human keratinocytes, birch bark extract induces keratinocyte differentiation by promoting the expression of differentiation markers such as keratin, type I cytoskeletal 10 (KRT 10) and involucrin (INV) as well as the adhesion protein transglutaminase.⁷ Also, It has been suggested that the purified triterpene extract derived from birch bark promotes keratinocyte differentiation by, at least in part, upregulating the non-selective transient receptor potential canonical (subtype) 6 (TRPC6) cation channel.^1,2

Absorption

For oleogel-S10 (Filsuvez, a preparation of birch bark extract), drug absorption was evaluated by measuring the systemic exposure to betulin, its main component. Betulin venous blood concentrations were measured using a dried blood spot bioanalytical method. In most subjects, betulin levels were below the quantitation limit (10 ng/mL). A minority of subjects had higher venous blood concentrations, no greater than 207 ng/mL. This venous blood concentration is similar to the one detected after ingesting betulin-containing foods.⁵

Volume of distribution

This pharmacokinetic property has not been studied.

Protein binding

Betulin, one of the main active components of birch bark extract, is >99.9% bound to plasma proteins.⁵

Metabolism

Approximately 99% of betulin, one of the main active components of birch bark extract, is metabolized in vitro within 5 hours. The most abundant betulin metabolite was formed through oxidation, methylation, and sulfation, and three other metabolites were formed by sulfation or glucuronidation.⁵ Betulin is expected to be metabolized mainly by non-CYP enzymatic pathways (75%). Betulin metabolism by CYP-mediated pathways (25%) is expected to be primarily performed by CYP3A4 and CYP3A5.⁵ In vitro studies have shown that betulin induces and inhibits several CYP enzymes; however, birch bark extract administered topically leads to negligible systemic exposure and no drug interaction is expected.⁵

Route of elimination

This pharmacokinetic property has not been studied.

Half-life

This pharmacokinetic property has not been studied.

Clearance

This pharmacokinetic property has not been studied.

Adverse Effects

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Toxicity

Overdose cases involving topical birch bark extract are unlikely. No overdose cases have been reported using a maximum amount of 69 g daily for more than 90 days.⁵ Toxicity information regarding the accidental ingestion of birch bark extract gel is not readily available.⁵ Patients experiencing an overdose should receive symptomatic and supportive measures.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Not Available

Food Interactions

No interactions found.

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International/Other Brands

Episalvan (Amryt Pharma) / Filsuvez (Amryt Pharma)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Filsuvez	Gel	100 mg/1g of gel	Cutaneous	Amryt Pharmaceuticals DAC	2023-03-15	Not applicable
Filsuvez	Gel	100 mg/1g of gel	Cutaneous	Amryt Pharmaceuticals DAC	2023-03-15	Not applicable
Filsuvez	Gel	100 mg/1g of gel	Cutaneous	Amryt Pharmaceuticals DAC	2022-07-15	Not applicable
Filsuvez	Gel	100 mg/1g of gel	Cutaneous	Amryt Pharmaceuticals DAC	2023-03-15	Not applicable
Filsuvez	Gel	100 mg/1g of gel	Cutaneous	Amryt Pharmaceuticals DAC	2022-07-15	Not applicable

Categories

Drug Categories

• Anti-Inflammatory Agents
• Anti-inflammatory Agents, Miscellaneous
• Biological Products
• Complex Mixtures
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inhibitors
• Plant Preparations
• Triterpenes
• Wound Healing

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

6NQM402G7Y

CAS number

84012-15-7

References

Synthesis Reference

Watson, JA., et al. (2021). Betulin-containing birch bark extracts and their formulation (U.S. Patent No. 11,083,733 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/b0/23/e2/b46df50cd8a12a/US11083733.pdf

General References

1. Schwieger-Briel A, Ott H, Kiritsi D, Laszczyk-Lauer M, Bodemer C: Mechanism of Oleogel-S10: A triterpene preparation for the treatment of epidermolysis bullosa. Dermatol Ther. 2019 Jul;32(4):e12983. doi: 10.1111/dth.12983. Epub 2019 Jul 2. [Article]
2. Woelfle U, Laszczyk MN, Kraus M, Leuner K, Kersten A, Simon-Haarhaus B, Scheffler A, Martin SF, Muller 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 Jan;130(1):113-23. doi: 10.1038/jid.2009.248. [Article]
3. Ghaffar KA, Daniels R: Oleogels with Birch Bark Dry Extract: Extract Saving Formulations through Gelation Enhancing Additives. Pharmaceutics. 2020 Feb 21;12(2). pii: pharmaceutics12020184. doi: 10.3390/pharmaceutics12020184. [Article]
4. 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 Jan 22;9(1):e86147. doi: 10.1371/journal.pone.0086147. eCollection 2014. [Article]
5. EMA Summary of Product Characteristics: Filsuvez (birch bark extract) gel for cutaneous use [Link]
6. EMA Summary of Product Characteristics: Episalvan (birch bark extract) gel for cutaneous use [Link]
7. EMA Assessment Report: Filsuvez (birch bark extract) gel for cutaneous use [Link]
8. Globe News Wire: European Commission Approves Filsuvez for the treatment of Dystrophic and Junctional EB [Link]
9. FDA Approved Drug Products: Filsuvez (birch triterpenes) topical gel [Link]
10. Chiesi Global Rare Diseases News Release: Chiesi Global Rare Diseases Receives FDA Approval for FILSUVEZ® (birch triterpenes) topical gel for the Treatment of Epidermolysis Bullosa [Link]

External Links

RxNav

1309815

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Burns	1
3	Completed	Treatment	Epidermolysis Bullosa (EB)	1
3	Completed	Treatment	Wound	2
2	Completed	Treatment	Accelerating the Epithelialization of Split Thickness Skin Graft	1
2	Completed	Treatment	Actinic Keratosis (AK)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Gel	Cutaneous
Gel	Cutaneous	100 mg/1g of gel

Prices

Not Available

Patents

Not Available

Properties

State

Liquid

Experimental Properties

Property	Value	Source
water solubility	Not soluble in water	EMA Assessment Report

Predicted Properties

Not Available

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

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Drug created at February 02, 2021 21:27 / Updated at February 14, 2024 00:55