Rohto Pharmaceutical Introduces a "Non-Neutralized" Azelaic Acid Serum: A Look at Its New Research and the "DRX AZA Clear Serum"

Using the "AZA Clear Serum" from the clinic-exclusive brand "DRX" as a case study, this article covers the data presented in the new research, how the serum differs from the conventional 20% cream in efficacy and irritation, and the key points of its ingredient design.

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Azelaic acid is a naturally occurring saturated dicarboxylic acid and an acidic substance that dissolves readily in oil. Reported effects include normalizing keratinization (normalizing skin turnover), antibacterial action that inhibits the growth of C. acnes and other bacteria, antioxidant action, skin-brightening action through tyrosinase inhibition, and anti-inflammatory action. Outside Japan, it is approved as a treatment for acne vulgaris and rosacea and is widely used as a pharmaceutical at concentrations of around 15–20%.

In Japan, however, it has not been approved as a pharmaceutical and has instead been distributed as a cosmetic ingredient. The reason it was not approved is said to be the strong skin irritation characteristic of azelaic acid. In particular, cases were observed in which Japanese skin could not tolerate the irritation from high-concentration formulations such as 20% or 15%.

To address this problem, Rohto Pharmaceutical conducted research over many years and, in 2011, launched the clinic-exclusive "DRX AZA Clear" as a formulation that Japanese users could also use comfortably. This is a dispersion-type cream containing approximately 20% azelaic acid. Later, in 2023, the company released "AZA Serum," said to be a virtually equivalent formulation, under its general-distribution brand "Dermacept RX," making it available for self-care as well.

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In recent years, as azelaic acid's sebum-controlling and acne-preventing effects have become widely known, manufacturers in Japan and abroad have released a succession of skincare products touting high concentrations such as 10% or 15%.

However, azelaic acid dissolves poorly in both water and oil. To stably incorporate it at high concentrations into water-based serums, the following methods have commonly been used:

1. Using derivatives: Making a derivative with improved water solubility, such as potassium azeloyl diglycinate, the main ingredient.
2. Neutralizing with an alkali (neutralized type): Adding sodium hydroxide or a similar agent to neutralize the acid and dissolve it in salt form.
3. Adding large amounts of surfactants: Using 10% or more surfactant to force it into solution.

The alkali-neutralized type has been especially common, but concerns have long been raised that neutralizing the acidic raw material impairs its inherent properties and may prevent it from delivering sufficient effects. Clinical data clearly verifying the efficacy of neutralized formulations against acne has been scarce, and their actual effectiveness has long remained unclear.

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In response to these questions, Rohto Pharmaceutical offered one perspective in a research release on September 8, 2024. The technology announced fully dissolves azelaic acid in the formulation without neutralizing it.

The ionization state of azelaic acid changes depending on pH conditions. In its un-neutralized state, it has the strongest bactericidal action and skin permeability, but low solubility in formulations. Adding an alkali to neutralize it (mono-neutralization or di-neutralization) increases its water solubility but reduces its bactericidal action and skin permeability. In other words, it was shown that neutralizing azelaic acid to dissolve it makes formulation easier but diminishes its inherent functions.

The company therefore developed a "non-neutralized 3% dissolved serum" and conducted a comparative study against the conventional "20% dispersion-type cream."

• Reduction in total lesion count (acne improvement): In the 12-week comparison, the 3% dissolved serum showed a level of improvement equivalent to the 20% dispersion-type cream. In particular, at an early stage after starting use (the 4-week mark), the serum tended to reduce lesion counts more quickly.
• Reduced irritation: Azelaic acid formulations tend to cause a tingling sensation when first used, but at the 2-week mark, the percentage of users who reported "no itching" was 23 points higher for the serum, and the percentage who reported "no irritation" was 18.4 points higher.

• About 4 times the penetration efficiency: In a test using excised human skin comparing skin permeability 24 hours after application, the 3% dissolved serum showed roughly 4 times the penetration efficiency of the 20% dispersion-type cream. The researchers suggest that because the azelaic acid is dissolved without being neutralized, it penetrates the skin efficiently even at a low concentration, allowing it to deliver equivalent or greater effects at nearly one-seventh the concentration.
• Bactericidal effect against C. acnes: The 3% dissolved serum showed a high bactericidal effect equivalent to that of the 20% dispersion-type cream.

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The product that appears to reflect this research technology is "DRX AZA Clear Serum," a medical-institution-exclusive product launched in July 2024.

Looking at the full ingredient list, DPG (dipropylene glycol) is the main ingredient, followed by water, the solvent ethoxydiglycol, the emulsifier Beneth-30, and then azelaic acid.

The formula is simple and free of fragrance, colorants, preservatives, and alcohol (ethanol), but DPG and ethoxydiglycol are used at high concentrations in the base, so the base itself is not exactly extremely low-irritation. It could be described as a bold formulation, with an ingeniously designed solvent system to fully dissolve the azelaic acid while keeping it un-neutralized.

When actually applied to the skin, the formulation produces its characteristic tingling, but this is milder than with the conventional 20% cream (AZA Clear, etc.). Compared with the strong stinging sensation that appears when applying the cream, the serum formulation's irritation feels gentler in onset.

For people with acne-prone skin or sebum problems who want to avoid oil-rich cream bases, the fact that it comes in a watery serum form while being expected to work on par with the conventional 20% cream is a major advantage.

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DRX AZA Clear Serum (26 mL) is currently offered as a medical-institution-exclusive product, and it is generally distributed by having customers visit a clinic that carries it, such as a cosmetic dermatology clinic, and purchase it there.

Considering that the conventional AZA Clear was later sold to the general public as "Dermacept RX AZA Serum," it is considered highly likely that this non-neutralized serum will also eventually be rolled out under a general-distribution brand such as Dermacept RX. However, since commercialization is expected to take a considerable amount of time, those who want to try it early will need to consult a clinic or check where it is available.