Encapsulation, Molecule Stabilizing Technology: Advances in the Treatment of Acne Vulgaris and Rosacea

Dermatological conditions contribute to approximately 1.79% of the global burden of diseases.1 According to the American Academy of Dermatology (AAD), 1 in 4 Americans has skin conditions.2 Acne, psoriasis, rosacea, and vitiligo are the most common conditions managed by dermatologists.3 While some skin conditions are transient, others may begin in childhood and continue into adulthood. Symptoms can wax and wane between quiescence and flares, significantly impacting a person’s quality of life and increasing the risk of depression.4

In 2013, skin diseases resulted in direct health care costs of $75 billion.5 The burden associated with skin conditions is significant and the impact on disability-adjusted life years is higher among women than men.6 Acne vulgaris is among the most common skin condition in the United States and both acne vulgaris and rosacea impose a significant impact on health-related quality of life.

Acne vulgaris, which affects up to 50 million people in the United States, is characterized by the formation of comedones, inflammatory papules, pustules, nodules, and cysts resulting from the obstruction and inflammation of hair follicles and sebaceous glands. Areas with dense populations of oil glands, such as the face, chest, and upper back are most commonly affected.7 Topical and/or oral antibiotics are routinely used to treat acne.8 The population most affected are young adults and adolescents between 11 and 30 years of age.9 The prevalence of acne vulgaris varies by age; it is rarely seen in pre-puberty and significantly increases with age after puberty (Figure 1).10

Rosacea, characterized by flushing, non-transient erythema, papules, pustules, telangiectasia, and phymatous changes, affects approximately 16 million individuals in the United States.11 Globally, rosacea is most commonly seen in adults 51 to 60 years of age (Figure 2).12 Rosacea primarily affects the face and negatively impacts the quality of life with its waxing and waning course.13 Approximately 70% of patients with rosacea have reported lower self-confidence and self-esteem.14

Limitations of Conventional Treatment Options for Dermatological Conditions

Treatment of acne vulgaris and rosacea involves topical and oral pharmacological agents as well as nonpharmacological agents. Clindamycin and erythromycin are topical antibiotic agents with anti-inflammatory properties commonly used to treat acne vulgaris.8 The risk of antibiotic resistance with clarithromycin and erythromycin is high, particularly when used as monotherapy.15 High rates of resistance by Cutibacterium acnes to these antibiotics have been reported globally.8 Current guidelines generally favor combination therapy with various agents including topical retinoids, hormonal therapy, and antimicrobial agents.16-19

The conventional treatment of rosacea has ranged from skincare and cosmetic treatments to topical, oral, and systemic therapies and laser- and light-based therapies. The treatment of choice must be individualized based on symptoms, severity, and presenting clinical features, although general management includes gentle skincare, sun protection, and trigger avoidance. Combination therapies include topical brimonidine with topical ivermectin, topical metronidazole with oral doxycycline, oral minocycline with topical azelaic acid, and topical clindamycin with tretinoin. Topical metronidazole, topical ivermectin, and topical azelaic acid used as monotherapy are appropriate for maintenance therapy.20

Topical agents have emerged as the cornerstone of treatment for many skin conditions as they enable a high concentration of drug delivery directly to the affected area and have relatively low systemic side effects.20 Traditionally, topical preparation includes creams, ointments, and solutions. Active ingredients of a topically-applied therapy do not diffuse through the skin barrier, resulting in limited therapeutic effect. Unmet medical needs persist for topically-applied agents with improved physicochemical properties of solubility, molecular weight, and pH stability to increase dermatological penetration.21

Novel drug formulations using a delivery system such as nanoparticles and liposomes have been developed to enhance the efficacy of topical agents and has shown to improve the treatment of acne, rosacea, and pruritus along with other dermatological conditions.21-24

Encapsulation: New Application of an Old Technology to Enhance Drug Delivery

Next-generation topical preparation utilizes various vehicles, including gels and foams, to enhance topical penetration of the active drug. Encapsulation and molecule stabilizing technology (MST) are recent advances that have improved the topical treatment of acne vulgaris and rosacea. Microencapsulation is a well-established technique in the cosmetic industry to enhance the efficacy and stability of active ingredients in cosmetic formulations. Encapsulation is a process of entrapping an active ingredient (core material) in a shell of a second material (wall material) and can enhance the stability of the active ingredient, protect the active ingredient against degradation, and allow for the controlled release of active ingredients. 25  

Encapsulation of active drug nanoparticles has the critical advantage of maintaining drug and increases penetration of the skin epidermis, allowing targeted delivery of the active ingredient while minimizing systemic side effects.25,26 Use of MST as a drug-delivery vehicle optimizes topical drug application.27 The clinical application of encapsulation and MST has resulted in the development of topical agents approved by the US Food and Drug Administration for the treatment of acne and rosacea.

Clinical Application of Encapsulation and Molecule Stabilizing Technology

Encapsulation is the technology behind a combination therapy of tretinoin 0.1% and benzoyl peroxide (BPO) 3% cream for the treatment of acne vulgaris in patients aged 9 years and older.28 Tretinoin and BPO are individually entrapped within silica-based microcapsules that prevent the degradation of tretinoin by BPO. These active ingredients are slowly released over time to provide a consistent drug concentration at the affected skin site.29

The tretinoin 0.1% and BPO 3% combination cream is the first encapsulated topical formulation for the treatment of acne. The FDA approval was based on 2 multicenter, double-blind, vehicle-controlled, phase 3 clinical trials (ClinicalTrials.gov Identifier: NCT03761784, NCT03761810). Safety and efficacy were evaluated in 858 patients aged 9 years and older with moderate-to-severe cases of acne vulgaris per Investigator Global Assessment (IGA) with 20 to 100 inflammatory lesions (papules, pustules, and nodules), 30 to 150 non-inflammatory lesions (open and closed comedones), and 2 or fewer facial nodules.29 Patients were randomly assigned in a 2 to 1 ratio to receive the tretinoin 0.1% and BPO 3% combination cream (n=571) or vehicle cream (n=287) once daily for 12 weeks.

The co-primary efficacy endpoints were the proportion of patients who achieved a 2-grade reduction from baseline and grade 0 or grade 1 on a 5-point IGA scale and absolute change in inflammatory and noninflammatory lesion counts from baseline after 12 weeks. Results from the clinical trials indicated that patients who received the combination therapy showed improved treatment outcomes compared with patients who received the vehicle (Table 1)29 for both co-primary endpoints.

The most commonly reported adverse effects were dryness, pigmentation, erythema, scaling, itching, burning, and stinging. Overall, the tretinoin 0.1% and BPO 3% combination cream was well-tolerated.29

Encapsulated BPO 5% is a topical cream in clinical development and used to treat moderate to severe papulopustular rosacea.30 The new drug application filing is based on 2 positive, identical phase 3, randomized, double-blind, multicenter, 12-week clinical trials that evaluated the safety and efficacy of encapsulated BPO 5%, compared with the vehicle in patients with papulopustular rosacea (ClinicalTrials.gov Identifier: NCT03448939, NCT03564145). Encapsulated BPO 5% demonstrated a statistically significant improvement for both co-primary endpoints (Table 2) in the 2 trials.30,31 

Encapsulated BPO 5% demonstrated a favorable safety and tolerability profile similar to the vehicle. The most common adverse reactions were mild or moderate erythema at the application site, application site pain, and application site pruritis.31

Advantages of encapsulation in topical applications
Minimal systemic effect and improved absorption into the epidermis to facilitate targeted drug delivery.

Another novel formulation is MST, a foam-based drug-delivery vehicle that optimizes the topical delivery of minocycline. Minocycline is a broad-spectrum antibiotic known for its efficacy in treating moderate-to-severe acne but its use was limited in some patients due to systemic side effects. However, minocycline was not previously available as a topical treatment due to its instability in traditional topical formulations.27 Minocycline topical foam 4% uses an MST platform to effectively deliver active ingredients in a foam-based vehicle. Minocycline topical foam 4% is approved by the FDA to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in adults and children 9 years of age and older. Minocycline topical foam 1.5% is approved to treat adults with rosacea.33


1. Karimkhani C, Dellavalle RP, Coffeng LE, et al. Global skin disease morbidity and mortality: an update from the global burden of disease study 2013JAMA Dermatol. 2017;153(5):406-412. doi:10.1001/jamadermatol.2016.5538

2. Lim HW, Collins SAB, Resneck JS Jr, et al. The burden of skin disease in the United States. J Am Acad Dermatol. 2017;76(5):958-972. doi:10.1016/j.jaad.2016.12.043

3. Lim HW, Collins SAB, Resneck JS Jr, et al. Contribution of health care factors to the burden of skin disease in the United States. J Am Acad Dermatol. 2017;76(6):1151-1160. doi:10.1016/j.jaad.2017.03.006

4. Greydanus DE, Azmeh R, Cabral MD, Dickson CA, Patel DR. Acne in the first three decades of life: an update of a disorder with profound implications for all decades of life. Dis Mon. 2021;67(4):101103. doi:10.1016/j.disamonth.2020.101103

5. Burden of skin disease. American Academy of Dermatology. Accessed April 16, 2022. https://www.aad.org/member/clinical-quality/clinical-care/bsd

6. Laughter MR, Maymone MBC, Karimkhani C, et al. The burden of skin and subcutaneous diseases in the United States from 1990 to 2017. JAMA Dermatol. 2020;156(8):874-881. doi:10.1001/jamadermatol.2020.1573

7. Oge LK, Broussard A, Marshall MD. Acne vulgaris: diagnosis and treatment. Am Fam Physician. 2019;100(8):475-484. 

8. Habeshian KA, Cohen BA. Current issues in the treatment of acne vulgaris. Pediatrics. 2020;145(suppl 2):S225-S230. doi:10.1542/peds.2019-2056L

9. Walsh TR, Efthimiou J, Dréno B. Systematic review of antibiotic resistance in acne: an increasing topical and oral threat. Lancet Infect Dis. 2016;16(3):e22-e32. doi:10.1016/S1473-3099(15)00527-7

10. Silverberg JI, Silverberg NB. Epidemiology and extracutaneous comorbidities of severe acne in adolescence: a U.S. population-based study. Br J Dermatol. 2014;170(5):1136-1142. doi:10.1111/bjd.12912

11. Buddenkotte J, Steinhoff M. Recent advances in understanding and managing rosacea. F1000Res. 2018;7:F1000 Faculty Rev-1885. doi:10.12688/f1000research.16537.1

12. Gether L, Overgaard LK, Egeberg A, Thyssen JP. Incidence and prevalence of rosacea: a systematic review and meta-analysis. Br J Dermatol. 2018;179(2):282-289. doi:10.1111/bjd.16481

13. Skin condition by the numbers. American Academy of Dermatology. Accessed April 16, 2022. https://www.aad.org/media/stats-numbers

14. Zhang H, Tang K, Wang Y, Fang R, Sun Q. Rosacea treatment: review and update. Dermatol Ther (Heidelb). 2021;11(1):13-24. doi:10.1007/s13555-020-00461-0

15. Huynh TT. Burden of disease: the psychosocial impact of rosacea on a patient’s quality of life. Am Health Drug Benefits. 2013;6(6):348-354.

16. Chon SY, Doan HQ, Mays RM, Singh SM, Gordon RA, Tyring SK. Antibiotic overuse and resistance in dermatology. Dermatol Ther. 2012;25(1):55-69. doi:10.1111/j.1529-8019.2012.01520.x

17. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-973.e33. doi:10.1016/j.jaad.2015.12.037

18. Asai Y, Baibergenova A, Dutil M, et al. Management of acne: Canadian clinical practice guideline. CMAJ. 2016;188(2):118-126. doi:10.1503/cmaj.140665

19. Nast A, Dreno B, Bettoli V, Bukvic Mokos Z, et al. European evidence-based (S3) guideline for the treatment of acne – update 2016 – short version. J Eur Acad Dermatol Venereol. 2016;30(8):1261-1268. doi:10.1111/jdv.13776

20. Na-Young Kang C, Shah M, Tan J. Rosacea: an update in diagnosis, classification and management. Skin Therapy Lett. 2021;26(4):1-8.

21. Wohlrab J. Topical preparations and their use in dermatology. J Dtsch Dermatol Ges. 2016;14(11):1061-1070. doi:10.1111/ddg.13151

22. Petrou I. New drugs and therapies in 2022: acne, rosacea, and pruritus. Dermatology Times. Published online January 24, 2022. Accessed April 15, 2022. https://www.dermatologytimes.com/view/new-drugs-and-therapies-2022-acne-rosacea-pruritus

23. Friedman AJ, Phan J, Schairer DO, et al. Antimicrobial and anti-inflammatory activity of chitosan-alginate nanoparticles: a targeted therapy for cutaneous pathogens. J Invest Dermatol. 2013;133(5):1231-1239. doi:10.1038/jid.2012.399

24. Pornpattananangkul D, Fu V, Thamphiwatana S, et al. In vivo treatment of Propionibacterium acnes infection with liposomal lauric acids. Adv Healthc Mater. 2013;2(10):1322-1328. doi:10.1002/adhm.201300002

25. Casanova F, Santos L. Encapsulation of cosmetic active ingredients for topical application–a review. J Microencapsul. 2016;33(1):1-17. doi:10.3109/02652048.2015.1115900

26. Blecher K, Nasir A, Friedman A. The growing role of nanotechnology in combating

infectious disease. Virulence. 2011;2(5):395-401. doi:10.4161/viru.2.5.17035

27. Foamix receives FDA approval of AMZEEQ™ topical minocycline treatment for millions of moderate to severe acne sufferers. News release. Published October 18, 2019. Accessed April 15, 2022. https://www.prnewswire.com/news-releases/foamix-receives-fda-approval-of-amzeeq-topical-minocycline-treatment-for-millions-of-moderate-to-severe-acne-sufferers-300941412.html

28. TWYNEO. Prescribing information. Sol-Gel Technologies Inc;2021. Accessed April 15, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214902s000lbl.pdf.

29. Del Rosso J, Levy-Hacham O, Mizrahi O. Efficacy and safety of microencapsulated benzoyl peroxide 3% and microencapsulated tretinoin 0.1% (E-Bpo/E-Atra) in acne vulgaris: results from two randomized controlled clinical trials. SKIN. 2021;5(1):s24. doi:10.25251/skin.5.supp.24

30. Sol-Gel announces positive top-line results from Epsolay® phase 3 program in papulopustular rosacea. News release. Published online July 8, 2019. Accessed April 15, 2022. https://ir.sol-gel.com/news-releases/news-release-details/sol-gel-announces-positive-top-line-results-epsolayr-phase-3

31. Del Rosso J, Bhatia N, Baldwin H, Stein Gold L, Brantman S. Critical evaluation of benzoyl peroxide in rosacea: old challenges and new clinical opportunities with encapsulated benzoyl peroxide. SKIN. 2022;6(2):s15. doi:10.25251/skin.6.supp.15

32. Amzeeq. Prescribing information. VYNE Pharmaceuticals Inc; 2020. Accessed April 15, 2022. https://www.amzeeq.com/sites/default/files/documents/vyne-amzeeq-prescribing-information.pdf

33. Zilxi. Prescribing information. VYNE Pharmaceuticals Inc; 2020. Accessed April 15, 2022. https://zilxi.com/sites/default/files/documents/prescribing-information.pdf

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Reviewed April 2022