Nanoemulsion

The Secret behind Ameluz®(aminolevulinic acid hydrochloride) gel, 10% Ameluz

Ameluz® (aminolevulinic acid hydrochloride) gel, 10% for topical use, also known as BF-200 ALA, is a unique oil-in-water (O/W) dispersion of nano-sized (< 50 nm diameter) vesicles composed of a lipid core surrounded by an emulsifying monolayer of phospholipids. This so called nanoemulsion (BF-200) belongs to the class of microemulsions.1 They are widely used in skin care and pharmaceutical formulations due to their biophysical properties, allowing for rapid tissue penetration.2 All ingredients of the nanoemulsion used in Ameluz® are well characterized standard ingredients, which have been in use in pharmaceutical and cosmetic products for many years.3 Hydrophilic 5-aminolevulinic acid (ALA) becomes soluble in the aqueous phase of the nanoemulsion, providing chemical stability of the active ingredient ALA, presumably by allowing it to adhere to the external, hydrophilic part of the nano-vesicles’ phosphatidylcholine monolayer.1 The nanoemulsion does not contain solid nanoparticles.

Freeze-fracture electron microscopy of the nanoemulsion (A,B) displaying the evenly distributed nano-sized vesicles which are believed to fuse with the lipid components of the stratum corneum, facilitating skin penetration of ALA. A schematic view of the nano-sized (< 50 nm diameter) vesicles composed of a lipid core surrounded by a monolayer of phospholipids in an aqueous solution (C).

 

Stabilization of ALA. The nanoemulsion in Ameluz® stabilizes ALA by binding ALA to the external, hydrophilic part of the nano-vesicles’ phosphatidylcholine monolayer. A schematic view of ALA adhering to one of the nano-sized vesicles (left), including the chemical entities that aid this interaction (middle). This process can also be observed under the microscope (freeze-fracture electron microscopy, right).

Besides its stabilizing properties, the nanoemulsion also aids the delivery of ALA directly to the epidermal layers. The mechanism by which ALA is transported through the skin presumably involves the fusion of vesicles with the lipid components of the stratum corneum, giving ALA the ability to overcome this barrier and enter the skin.

Pre-clinical data of PpIX distribution 3 and 12 hours after application of Ameluz® in a porcine ex vivo skin model.1 Samples were removed at the time points indicated and assessed for the induction of PpIX. PpIX (red), basal cell layer (blue line) (A,B). The penetration depth of Ameluz® was analyzed by the fluorescence intensity of PpIX along several virtual vertical lines (C). The virtual line was drawn at various points on each of the skin sections and the maximal depth of the epidermis (border = basal membrane) was determined at the same points (grey bars; n = 7 median ± standard deviation). The black line with diamond-shaped symbols represents the maximal vertical extent of the epidermis (n = 7, median ± standard deviation).

The penetration properties of Ameluz® were also demonstrated in pre-clinical experiments with an ex vivo model of human skin. Schmitz et al., 2016 have established a culturing chamber to analyze the penetration depth and PpIX induction of Ameluz® (BF-200 ALA). Samples were taken from healthy individuals during upper eyelid surgery exposed to either Ameluz® or a 20% ALA ointment (non-ionic hydrophilic cream).4

Spatial distribution of PpIX in the human epidermis. PpIX-fluorescence was quantified from microscopic pictures and plotted against the distance from the basal membrane. a–d show the spatially stratified signal intensities for BF-200 ALA (red line), 20% ALA cream (green line) and placebo gel (blue line) after 1, 3, 5 and 12 h, respectively. Data are expressed as median values of n = 8 (BF-200 ALA), n = 3 (Placebo gel) and n = 6 (20% ALA cream) independent experiments with skin material from 10 different patients. Error bars depict median absolute deviation (MAD). Data points were tested for statistical significance using Kruskal–Wallis ANOVA-on-ranks with Dunn’s post-hoc test.*p < 0.05, (BF = BF-200 ALA; Pl = Placebo). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)4
1 Maisch et al., Exp. Derm 2010; 19: e302-e305 9 2 Wu et al., 2013 J Drug Target. 2013 May;21(4):321-7. 3 Ameluz® Prescribing Information 4 Schmitz et al., Photodiagnosis Photodyn Ther. 2016 Jun;14:40-6.

 

For Ameluz® full prescribing information and BF-RhodoLED® user manual please refer to: www.dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=650daa9f-aeec-49ce-95b9-5fa20b988afd

Important Safety Information

AMELUZ® (aminolevulinic acid hydrochloride) gel, 10% with BF-RhodoLED® lamp

AMELUZ®, containing 10% aminolevulinic acid hydrochloride, is a non-sterile gel formulation for topical use only. Not for ophthalmic, oral, or intravaginal use.

AMELUZ®, in conjunction with lesion preparation, is only to be administered by a health care provider. Photodynamic therapy with AMELUZ® involves preparation of lesions, application of the product, occlusion and illumination with BF-RhodoLED®. The application area should not exceed 20 cm2 and no more than 2 grams of AMELUZ® (one tube) should be used at one time. Lesions that have not completely resolved shall be retreated 3 months after the initial treatment. Refer to BF-RhodoLED® user manual for detailed lamp safety and operating instructions. Both patient and medical personnel conducting the PDT should adhere to all safety instructions.

Ameluz® shall not be used by persons who have known hypersensitivity to porphyrins or any of the components of AMELUZ®, which includes soybean phosphatidylcholine. Ameluz® should also not be used for patients who have porphyria or photodermatoses.

Transient Amnestic Episodes have been reported during postmarketing use of AMELUZ® in combination with photodynamic therapy (PDT). If patients experience amnesia or confusion, discontinue treatment. Advise them to contact the healthcare provider if the patient develops amnesia after treatment.

Eye exposure to the red light of the BF-RhodoLED® lamp during PDT must be prevented by protective eyewear. Direct staring into the light source must be avoided. AMELUZ® increases photosensitivity. Patients should avoid sunlight, prolonged or intense light (e.g., tanning beds, sun lamps) on lesions and surrounding skin treated with AMELUZ® for approximately 48 hours following treatment whether exposed to illumination or not.

AMELUZ® has not been tested on patients with inherited or acquired coagulation disorders. Special care should be taken to avoid bleeding during lesion preparation in such patients. Any bleeding must be stopped before application of the gel. AMELUZ® should not be used on mucous membranes or in the eyes.

Local skin reactions at the application site were observed in about 99.5% of subjects treated with AMELUZ® and narrow spectrum lamps. The very common adverse reactions (≥10%) during and after PDT were application site erythema, pain/burning, irritation, edema, pruritus, exfoliation, scab, induration, and vesicles. Most adverse reactions occurred during illumination or shortly afterwards, were generally of mild or moderate intensity, and lasted for 1 to 4 days in most cases; in some cases, however, they persisted for 1 to 2 weeks or even longer. Severe pain/burning occurred in up to 30% of treatments.

There have been no formal studies of the interaction of AMELUZ® with other drugs. Concomitant use of the following photosensitizing medications may increase the phototoxic reactions after PDT: St. John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones, and tetracyclines.

There are no available data on AMELUZ® use in pregnant women to inform a drug associated risk. No data are available regarding the presence of aminolevulinic acid in human milk, the effects of aminolevulinic acid on the breastfed infant or on milk production. Safety and effectiveness in pediatric patients below the age of 18 have not been established as AK is not a condition generally seen in the pediatric population. No overall differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Please read the US Full Prescribing Information for Ameluz® and/or US User Manual of BF-RhodoLED® lamp available together at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=650daa9f-aeec-49ce-95b9-5fa20b988afd.

You are encouraged to report side effects of Ameluz®. Please contact Biofrontera Inc. at 1-844-829-7434 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.