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by Nat Jones, RPh, FAPC, Clinical Compounding Pharmacist, Clinical Services
Production of melanin in the skin takes place in the organelles of melanocytes called melanosomes. Melanocytes have dendritic extension that transfer melanin to up to 40 keratinocytes. Most people have a baseline level of melanin production and the ability to produce more in response to UV exposure.
The physiology of melanin production helps us understand how many agents work to help prevent its formation. There are two types of melanin, eumelanin (browns and black) and pheomelanin (reds and yellows). Melanogenesis start with conversion of the amino acid, L-tyrosine, to dopaquinone by the enzyme tyrosinase. From there, our genetics guide the production of additional enzymes used, which determine the pathway, quantity and type of melanin made. Our phenotypical skin color appearance is the result of the final mixture of both eumelanin and pheomelanin. Albinos genetically cannot produce eumelanin, only pheomelanin, thus they have very pale complexions and are more vulnerable to UV exposure (sun burn, skin cancer) because eumelanin offers protection from UVB rays, but not pheomelanin.1
DISORDER TYPES
There are several types of pigmentation disorders. Hypopigmentation is less common than hyperpigmentation. While vitiligo, an autoimmune disease, is the most severe form, hypopigmentation is seen in other conditions such as pityriasis alba, tinea versicolor, post-inflammatory hypomelanosis, atopic dermatitis, psoriasis and guttate parapsoriasis.
Forms of hyperpigmentation include melasma, cholasma, solar lentigines (age spots), ephelides (freckles) and post-inflammatory hyperpigmentation (PIH). Often seborrheic keratoses will exhibit hyperpigmentation as well.
As compounding pharmacists, we now have a variety of chemical tools at our disposal to utilize in the treatment of hyperpigmentation. The number of ingredients used to compound formulas for hyperpigmentation has grown substantially over time.
Hydroquinone (HQ) is and has been the gold standard API for skin lightening. It is easily oxidized so adequate antioxidant coverage is needed when formulating, which can vary based on potency. Arbutin (alpha) is hydrolyzed to hydroquinone in the skin, by skin bacteria like Staphylococcus aureus and Staphylococcus epidermidis and enzymatically converted by tyrosinase.2,3 Dermatological best practices recommend rotation away from HQ therapy after three months, for three months, because of the possibility of an adverse event known as ochronosis from long-term use. Exogenous ochronosis, although rare, can be a permanent form of dyschromia that is very difficult to treat.4
Other interesting agents of note include ascorbic acid, which reduces o-dopaquinone back to dopa; niacinamide that inhibits transfer of melanin from the melanocytes to the keratinocytes; tranexamic acid that decreases melanocyte stimulating hormone production; and methimazole that inhibits peroxidase. Several agents, azelaic acid (and the cosmetic form, potassium azelaoyl diglycinate), resveratrol, licorice root, lactic acid, ferulic acid and mequinol, all inhibit tyrosinase.
Formulas with stable combinations of ingredients exhibiting multiple mechanisms of action (MOAs) will likely offer a synergistic advantage in clinical efficacy over single entity formulas. The obvious disadvantage of a combination approach is if adverse events occur it can be unclear which agent is the offensive one.
If PCCA members with Clinical Services access have questions about compounding our formulas, they can contact our clinical compounding pharmacists at 800.331.2498.
A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.
Saka B, Akakpo SA, Teclessou JN, et al., Skin cancers in people with albinism in Togo in 2019: results of two rounds of national mobile skin care clinics. BMC Cancer. 2021;21(1):26. January 5, 2021, doi:10.1186/s12885-020-07747-8
Bang SH, Han SJ, Kim DH. Hydrolysis of arbutin to hydroquinone by human skin bacteria and its effect on antioxidant activity. .J Cosmet Dermatol. 2008;7(3):189-193. doi:10.1111/j.1473-2165.2008.00387
Garcia-Jimenez A, Teruel-Puche JA, Berna J, et al., Action of tyrosinase on alpha and beta-arbutin: A kinetic study. PLoS ONE 12(5): e0177330 2017, https://doi.org/10.1371/journal.pone.0177330
Bhattar PA, Zawar VP, Godse KV, Patil SP, Nadkarni NJ, Gautam MM. Exogenous Ochronosis. Indian J Dermatol. 2015;60(6):537-543. doi:10.4103/0019-5154.169122