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The BF-200 nanoemulsion – it is all about the formulation

Topical use of 5-aminolaevulinic acid (5-ALA) in the skin presents two pharmaceutical challenges:

Challenge 1:

Stabilisation of the 5-ALA molecules

Background: 5-ALA molecules are chemically very unstable in aqueous solution. This is the reason why classic formulations with 5-ALA have a very short shelf life.


 

THE SOLUTION

Solution 1:

5-ALA dissolves in the aqueous phase of the nanoemulsion and becomes attached to the hydrophilic part of the phospholipid monolayer on the outside of the nanovesicles. This prevents the free mobility of the 5-ALA molecules and thus significantly increases their chemical stability.1 In practice the stability of Ameluz® (78 mg/g 5-aminolaevulinic acid gel) when unopened is 24 months and as much as 12 weeks even  after a tube has been opened.

THE CHALLENGE

Challenge 2:

Transport of 5-ALA molecules through the stratum corneum

Background: The stratum corneum forms a natural barrier against the environment. It is composed of keratinized, dead corneocytes, which are embedded in lipid bilayers. The lipid stratum corneum cannot easily be penetrated by the strongly charged (polar) and therefore hydrophilic 5-ALA molecules.2

THE SOLUTION

Solution 2:

Upon contact with the skin, the lipid components of the nanovesicles fuse with the lipid bilayer of the stratum corneum. It is assumed that this temporarily makes the skin barrier more fluid and thus more permeable for the 5-ALA molecules. In this way the penetration of the hydrophilic active agent molecules through the lipid-containing stratum corneum is improved, which allows a distribution into the lowest epidermal layers3: 5-ALA can thus penetrate to the basement membrane and be metabolized throughout the epidermis to the active substance protoporphyrin IX (PpIX) (see Fig. 2).3 This enables the efficient treatment of deep-seated neoplastic cells. The significantly greater synthesis of PpIX in neoplastic cells favours the selectivity of the therapy.1,4 The therapeutic success of this concept has been proven by the convincing clinical efficacy of Ameluz®.5-8

THE CHALLENGE

The solution: The nanoemulsion BF-200

The patented nanoemulsion BF-200 belongs to the group of microemulsions, which are widely used in skin care products and pharmaceuticals. BF-200 is an oil-in-water emulsion: The lipid phase consists of a large number of small vesicles with a diameter in the nanometer range (approx. 15-30 nm), which are dissolved in the aqueous phase. The vesicles consist of a liquid lipid core enveloped by a phospholipid monolayer.

Phospholipids have a lipophilic tail and a hydrophilic head. The heads are electrically charged and directed towards the outside of the vesicles (see Fig. 1).

The 5-ALA molecules are also electrically charged and, according to the postulated mechanism, can bind to the charged phospholipid heads of the nanovesicles via electrostatic interactions (see Fig. 1).

Figure 1: Structure of BF-200 nanovesicles with bound 5-ALA molecules.
Figure 2: Fusion of the BF-200 ALA nanovesicle with the stratum corneum disrupting the lipid bilayer, allowing the released ALA molecules to penetrate the epidermis through to the basal membrane.

References

  1. Reinhold U. Future Oncol 2017;13:2413-2428.
  2. Uehlinger et al. J Photochem Photobiol B 2000;54:72-80.
  3. Schmitz L et al. Photodiagnosis Photodyn Ther 2016;14:40-46.
  4. Schulten R et al. Naunyn Schmiedebergs Arch Pharmacol 2012;385:969-979.  
  5. Szeimies RM et al. Br J Dermatol 2010;163:386-394.
  6. Dirschka T et al. Br J Dermatol 2012;166:137-146.
  7. Dirschka T et al. Br J Dermatol 2013;168: 825-836.
  8. Reinhold U et al. Br J Dermatol 2016;175:696-705.

 

 

Item Number UKBF-2022-006g-V01, Date of Preparation: September 2022