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Attacking Acne: OTC Topical Treatments

Contact Author Peter Thomas Roth, Peter Thomas Roth Clinical Skin Care, New York
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Read this article in its entirety in the October 2020 digital edition. . .

The U.S. Food and Drug Administration (FDA) defines acne as a disease involving the oil glands and hair follicles of the skin that is manifested by blackheads, whiteheads, acne pimples and acne blemishes.1 Acne is considered one of the most common skin disorders. More than 90% of the world's population is affected by acne at some point in life, and women are more frequently affected by adult acne than men.2 It is estimated that billions of dollars are spent every year for the treatment of acne.3With increased cosmetic formulation complexities and market demand for tailored skin care, the anti-acne sector has seen great growth in the past decade. The same trend is projected to continue into the foreseeable future.

An array of acne treatment options is available, ranging from alternative medicine and physical procedures to prescription and over-the-counter (OTC) drugs. Alternative medicines include natural extracts that exhibit antioxidant and antimicrobial activity, as well as help to dry out the skin to combat overactive sebum production. Physical treatments include comedone extraction, cryotherapy, electrocauterization and UV treatments.4

Prescription drugs include hormonal medications, antibiotics and topical treatments. Oral contraceptives, for example, are the most widely used prescription hormonal treatments to suppress the sebum production associated with acne conditions.5 Oral antibiotics are also prescribed to systemically treat acne, whereas topical antibiotics provide localized care. In both applications, the regimen is often coupled with additional antimicrobial agents in order to minimize the risk of developing drug resistance.6

OTC topicals for acne are limited to those specified in the U.S. FDA acne monograph.7 This article will focus on these treatments and their formulations in the cosmetic industry.

Acne Development

The development of acne involves increased sebum production, diminished desquamation and Cutibacterium acnes (C. acnes, previously Propionibacterium acnes) proliferation, which leads to inflammation.8 Increased sebum production can be attributed to hormonal changes or a growth spurt. In combination with diminished desquamation, increased sebum eventually leads to C. acnes proliferation. Diminished desquamation causes an accumulation of corneocytes—a process referred to as comedogenesis. Once a comedone or clogged pore is formed, an ideal growth environment for C. acnes is generated.

C. acnes is an anaerobic, Gram-positive bacteria that is present on all skin types.9 It thrives in a closed, lipid-rich anaerobic environment. Once C. acnes begins to proliferate inside a clogged pore, local inflammation occurs, which leads to Acne vulgaris.

OTC Acne Actives

The U.S. FDA acne monograph lists benzoyl peroxide, resorcinol, resorcinol monoacetate, salicylic acid and sulfur as Generally Regarded As Safe and Effective (GRASE) active ingredients for OTC topical acne drug products. Benzoyl peroxide, salicylic acid and sulfur can be used as stand-alone anti-acne actives. Resorcinol and resorcinol monoacetate can only be used in combination with sulfur.1 Between benzoyl peroxide, salicylic acid and sulfur, benzoyl peroxide is reported to be the most aggressive against acne and, at the same time, most irritating on the skin. Salicylic acid is milder than benzoyl peroxide, whereas sulfur is the gentlest on skin.

Benzoyl peroxide: Benzoyl peroxide provides both antimicrobial and comedolytic activity. Its ability to release oxygen makes it especially effective against the anaerobic Gram-positive bacteria C. acnes. The comedolytic activity not only reduces the number of comedones on the skin, but it also exposes C. acnes inside the comedone to benzoyl peroxide and oxygen. Figure 1 shows the chemical structure of benzoyl peroxide.

In its pure form, benzoyl peroxide is a white solid that is insoluble in water. The difficulty of working with benzoyl peroxide lies in its inverse relationship between solubility and stability.10, 11 Benzoyl peroxide is most soluble in polyethylene glycol and isopropyl myristate. Under these solvent conditions, benzoyl peroxide decomposes rapidly; within one month.12 In order to overcome this combination of instability and insolubility, benzoyl peroxide is often provided as a concentrated dispersion form in an aqueous gel for use in cosmetic formulas. In the dispersion form, benzoyl peroxide is present as a micronized solid particle. Even though benzoyl peroxide is applied to the acne-ridden area in its solid form, it readily incorporates itself in the acneic region due to its hydrophobic nature. The lipid-rich environment around the acne pores provides an ideal condition for benzoyl peroxide incorporation.

Although effective against acne, benzoyl peroxide is also known for its potential to irritate the skin. The U.S. FDA declared, in the 2010 amended final acne monograph, that benzoyl peroxide at 2.5% to 10% is safe for acne treatments. In addition to potential skin irritation, other disadvantages of using benzoyl peroxide are the resulting bleach stains and discoloration that can happen when this ingredient comes into contact with fabric.

Salicylic acid: Similar to benzoyl peroxide, salicylic acid also provides both antimicrobial13 and comedolytic activity.14 The name salicylic acid comes from the Latin word salix, which means “willow tree.” Willow bark is a natural source of salicylic acid. In ancient medicine, chewing willow bark was used to help ease pain and reduce fever. Similarly, salicylic acid exhibits soothing and anti-inflammatory effects in skin. It belongs in the same family of molecules as the anti-inflammatory drug acetylsalicylic acida. Compared with benzoyl peroxide, salicylic acid is considered a less aggressive acne treatment. It is less irritating to skin and effective against blackheads and whiteheads, whereas benzoyl peroxide is effective against more developed acne conditions, such as pustules or pimples. The U.S. FDA provides effective use levels of 0.5% to 2% salicylic acid for acne treatments.

The International Union of Pure and Applied Chemistry (IUPAC) name for salicylic acid is 2-hydroxybenzoic acid. Because the benzene ring connects the carboxylic acid and the hydroxyl group within the salicylic acid structure (see Figure 2), it is considered a pseudo beta hydroxy acid. The name beta hydroxy indicates the hydroxyl (-OH) group is located on the second carbon (beta position), away from the carbonyl (C=O) carbon. However, the first carbon (alpha position) and the second carbon (beta position) are part of the aromatic benzyl group, which influences the acidic potential at the beta position as well as the carboxylic acid (COOH).

Instead of beta hydroxy acid, a more accurate term for salicylic acid is phenolic aromatic acid.15 The phenolic aromatic acid character lowers the pKa (-log of acid dissociation constant) value. Salicylic acid has a pKa value of 2.97, whereas the simplest beta hydroxy acid, beta-hydroxypropionic acid (see Figure 3), has a pKa value of 4.51. At pH = pKa, 50% of salicylic acid is present in its neutral acid form and the remaining 50% is present in its anionic (negative charge) form. When the pH is increased by one unit to 3.97, only 10% of salicylic acid is in its neutral acid form and 90% is in its anionic form. Comedolytic activity requires that salicylic acid is in its neutral acid form. Therefore, at a pH level of 3.97, the effective concentration of salicylic acid is only one-tenth of the level of salicylic acid added to the formula. At a pH level of 4.97, only one-hundredth of the level of salicylic acid would demonstrate comedolytic activity.

The water solubility of salicylic acid has an inverse relationship with increasing pH value. At the pH conditions where salicylic acid exhibits optimal comedolytic activity, the water solubility is the poorest. In order to optimize formula compatibility, pre-blending salicylic acid in a combination solvent system including glycols, alcohols and/or solubilizers is recommended.

. . .Read more in the October 2020 digital edition. . .

References

  1. FDA OTC acne final monograph. (Mar 4, 2010). FDA: U.S. Food & Drug Administration. 56 FR 41019, as amended at 75 FR 9776.
  2. Skroza, N., et al. (2018). Adult acne versus adolescent acne. J Clin Aesthet Dermatol 11(1) 21–25.
  3. Bhate, K. and Williams, H.C. (2013). Epidemiology of acne vulgaris. Br J Dermatol 168(3) 474-485.
  4. Fox, L., et al. (2016). Review: treatment modalities for acne. Molecules 21(8) 1063.
  5. Gollnick, H. (2003). Current concepts of the pathogenesis of acne: implications for drug treatment. Drugs 63(15) 1570-1596.
  6. Hauk, L. (2017). Acne vulgaris: treatment guidelines from the AAD. Am Fam Physician 95(11) 740-741.
  7. FDA (accessed 2020, Aug 26). Rulemaking history for OTC acne drug products. Available at https://www.fda.gov/drugs/status-otc-rulemakings/rulemaking-history-otc-acne-drug-products.
  8. Gollnick, H., et al (2003). Management of acne: A report from a global alliance to improve outcomes in acne. J Am Acad Dermatol 49(1 Suppl) S1-37.
  9. Webster, G.F. (2001) Acne Vulgaris and rosacea: Evaluation and management. Clin Cornerstone 4(1) 15-22.
  10. Chellquist, E.M. and Gorman, W.G. (1992) Benzoyl peroxide solubility and stability in hydric solvents. Pharm Res 9(10) 1341-1346.
  11. Sarquis, A.M., et al. (2008) Investigating the stability of benzoyl peroxide in over-the-counter acne medications. J Chem Educ 85(12) 1655-1657 (2008)
  12. Bollinger, J.N, et al. (1977) Benzoyl peroxide stability in pharmaceutical gel preparations. J Pharm Sci 66(5) 718-722.
  13. Gershon, H. and Parmegiani, R. (1962)Antimicrobial activity of 8-quinolinols, salicylic acids, hydroxynaphthoic acids, and salts of selected quinolinols with selected hydroxy-acids. Appl Microbiol 10(4) 348-353.
  14. Arif, T. (2015) Salicylic acid as a peeling agent: a comprehensive review. Clin Cosmet Investig Dermatol 26(8) 455-461.
  15. Yu, R.J. and Van Scott, E.J. (1997)Salicylic acid: not a beta-hydroxy acid. Cosmet Derm 10(27).

a Aspirin, Bayer AG

 

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Figure 1. Chemical structure of benzoyl peroxide

Chemical structure of benzoyl peroxide

Figure 2. Chemical structure of salicylic acid

Chemical structure of salicylic acid

Figure 3. Chemical structure of beta-hydroxypropionic acid

Chemical structure of beta-hydroxypropionic acid

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