Tretinoin Formulation: From Microsponges to Polymeric Emulsion
The history of tretinoin and its use in dermatology is a testament both to the drug’s well-established efficacy and its potential to cause skin irritation. Over more than four decades, the drug that launched the retinoid class into the market has been used in the topical management of acne, either alone or in combination. In fact, current consensus acne treatment guidelines rely heavily on retinoids, as they address several aspects of acne pathogenesis— they are comedolytic, resolve the precursor microcomedone, and are anti-inflammatory— without posing any risk for antibiotic resistance.1
However, topically applied tretinoin has been associated with skin dryness, erythema, and even development of dermatitis. This legacy of irritation may largely derive from the earliest vehicles of the drug, which were formulated with a high concentration of active drug solubilized in solutions that contained several irritating excipients such as alcohol.2 Innovation led to the formulation of tretinoin in sponge-like, porous, polymeric microspheres that encapsulate the drug and deliver it gradually, in a vehicle where tretinoin has limited solubility.3 Microsponge delivery of tretinoin was associated with decreased irritation and improved drug stability. Subsequent formulation advancements attempted to further improve the patient experience with tretinoin.
The latest advancement in vehicle formulation for tretinoin has brought prescribers the first topical lotion formulation of tretinoin 0.05% (Altreno, Ortho Dermatologics). The novel lotion formulation incorporates a polymeric honeycomb matrix that helps provide a uniform distribution of both active and moisturizing/hydrating ingredients. Phase 3 data show a 52% percent reduction in inflammatory lesions at week 12 compared to baseline with the use of tretinoin 0.05% lotion; statistically significant reduction in comedonal lesions as early as week 4, and a 46% reduction by week 12.4 More importantly, the new formulation was very well tolerated in studies.
As discussed ahead, data show specific skin-supporting benefits associated with the novel lotion formulation of tretinoin. Specifically, topical application of the lotion was associated with rapidly increased skin hydration and decreased trans-epidermal water loss (TEWL)—an important measure of barrier function—as measured by Corneometer® and Tewameter®, respectively. The documented barrier-supporting effects of the lotion vehicle are welcomed for acne, as it is well established that a properly functioning barrier is essential to re-establishing healthy skin. A wide range of patients with various skin types may appreciate the hydrating effects of an easily applied topical lotion. Additionally, the lotion formulation may be especially attractive to those women who may wish to apply make-up over their topical medications.
With these thoughts in mind, dermatology providers can see potential benefit in the availability of a topical lotion formulation of tretinoin with proven efficacy and excellent tolerability.
However, topically applied tretinoin has been associated with skin dryness, erythema, and even development of dermatitis. This legacy of irritation may largely derive from the earliest vehicles of the drug, which were formulated with a high concentration of active drug solubilized in solutions that contained several irritating excipients such as alcohol.2 Innovation led to the formulation of tretinoin in sponge-like, porous, polymeric microspheres that encapsulate the drug and deliver it gradually, in a vehicle where tretinoin has limited solubility.3 Microsponge delivery of tretinoin was associated with decreased irritation and improved drug stability. Subsequent formulation advancements attempted to further improve the patient experience with tretinoin.
The latest advancement in vehicle formulation for tretinoin has brought prescribers the first topical lotion formulation of tretinoin 0.05% (Altreno, Ortho Dermatologics). The novel lotion formulation incorporates a polymeric honeycomb matrix that helps provide a uniform distribution of both active and moisturizing/hydrating ingredients. Phase 3 data show a 52% percent reduction in inflammatory lesions at week 12 compared to baseline with the use of tretinoin 0.05% lotion; statistically significant reduction in comedonal lesions as early as week 4, and a 46% reduction by week 12.4 More importantly, the new formulation was very well tolerated in studies.
As discussed ahead, data show specific skin-supporting benefits associated with the novel lotion formulation of tretinoin. Specifically, topical application of the lotion was associated with rapidly increased skin hydration and decreased trans-epidermal water loss (TEWL)—an important measure of barrier function—as measured by Corneometer® and Tewameter®, respectively. The documented barrier-supporting effects of the lotion vehicle are welcomed for acne, as it is well established that a properly functioning barrier is essential to re-establishing healthy skin. A wide range of patients with various skin types may appreciate the hydrating effects of an easily applied topical lotion. Additionally, the lotion formulation may be especially attractive to those women who may wish to apply make-up over their topical medications.
With these thoughts in mind, dermatology providers can see potential benefit in the availability of a topical lotion formulation of tretinoin with proven efficacy and excellent tolerability.
Leon H. Kircik MD
Icahn School of Medicine at Mount Sinai, New York, NY
Indiana University Medical Center, Indianapolis, IN
Physicians Skin Care, PLLC, Louisville, KY DermResearch, PLLC, Louisville, KY
Skin Sciences, PLLC, Louisville, KY
Icahn School of Medicine at Mount Sinai, New York, NY
Indiana University Medical Center, Indianapolis, IN
Physicians Skin Care, PLLC, Louisville, KY DermResearch, PLLC, Louisville, KY
Skin Sciences, PLLC, Louisville, KY
REFERENCES
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol 2016;74(5):945-73.
- Ceilley RI. Advances in topical delivery systems in acne: new solutions to address concentration dependent irritation and dryness. Skinmed 2011;9(1):15-21.
- Embil K, Nacht S. The microsponge delivery system (MDS): a topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives. J Microencapsul 1996;13:575-588.
- Tyring SK, Kircik L, Pariser DM, et al. Novel Tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of efficacy and safety in patients aged 9 years and older. J Drugs Dermatol 2018;17(10):602-609.
The Microsponge Delivery System (MDS) for Tretinoin: A First Attempt at Reducing Irritation
The Microsponge Delivery System (MDS) is a controlled drug delivery system that encapsulates the active drug, releasing it over time; and in response to a trigger such as rubbing, changes in pH, or increased temperature. The technology was developed over 30 years ago,1 and is widely used in cosmetics, skin care products available over-the-counter or through prescription, and sunscreens.2It consists of porous, polymeric microspheres (polyol-prepolymer-2) forming multiple interconnecting spaces that serve as a drug reservoir and mimicking a rigid sponge. Microspheres vary in size from 5-300μm and the sizes of these porous structures determine the amount and rate of drug release. For example, a typical 25μm sphere can have as many as 250,000 pores. Microspheres do not penetrate the skin; they sit on top of the skin and slowly release tretinoin to potentially reduce any irritation. The empty spheres may stay on the skin and collect lipophilic materials such as sebum and be washed away when the skin is cleansed.Microspheres delay the onset of irritation, but do not reduce the cumulative irritation when compared with other tretinoin formulations.3 Another safety concern is the potential bacterial contamination of materials entrapped in the microsponge. Bacteria cannot penetrate into the tunnel structure of the microsphere because the pore diameter, which ranges from 0.007 to 0.2μm, is smaller than bacteria. In addition to any drug delivery benefits, they are capable of absorbing skin secretions, reducing oiliness and shine from the skin. In the case of tretinoin microsphere formulations, the drug is encapsulated in copolymer particles measuring 17-27μm and released gradually into the skin.Additional benefits of the MDS include improved photostability, improved compatibility with benzoyl peroxide (BP), and reduced irritation potential. Tretinoin formulations (ie, gels, creams, and lotions) have been reported to be unstable on the skin under bright artificial light or sunlight. When combined with a strong oxidizing agent such as BP and antibiotic such as erythromycin, and subjected to fluorescent light for 24 hours, tretinoin photodegradation in tretinoin 0.025% gel increased to 89% and 95%.4,5 Tretinoin in a microsphere formulation did not undergo such degradation; 98% of tretinoin tested remained stable after 24 hours exposure to fluorescent light, incandescent light, or darkness.5 A similar protective effect was seen after exposure to simulated solar UV irradiation for 6 hours; 84% of the initial tretinoin remained stable in the microsphere formulation, compared with only 10% in tretinoin 0.025% gel.6 Irradiation of a tretinoin microsphere-BP-erythromycin combination resulted in a 94% to 95% tretinoin recovery rate after 8 hours and 86% to 87% recovery rate after 24 hours of exposure to incandescent or fluorescent light.5After 6 hours of simulated solar light, 81% of the combination remained stable compared with 0% in tretinoin 0.025% gel.6 The practical benefits of these findings were demonstrated in a phase 4 study of tretinoin microsphere 0.04% plus BP 5% wash, where patients who cleansed their face with BP 5% wash followed by tretinoin each morning and those who cleansed in the morning and applied tretinoin microsphere 0.04% gel each evening had a similar response.7Application of the MDS to the skin has demonstrated the ability to reduce the irritancy of tretinoin. However, one disadvantage of tretinoin microsphere 0.1% gel is its rough or ‘gritty’ texture when spread onto the skin, due to the nature of the microsponges and some patients find this unpleasant. Also, a ‘burst effect’ can occur as tretinoin is released from microspheres attributed to the deposition of drug at or close to the outermost parts of the microsphere walls.8 This burst delivery of tretinoin may cause drying and peeling that could progress to uncomfortable scaling and redness of the skin and impact adherence. This new technology may be able to improve on the advances already made with the MDS system.
Micronization of Tretinoin
The role of particle size reduction and particle engineering is another important aspect of formulation development in acne. Micronization is a valuable technique for products with poor water solubility and bioavailability. It increases the dissolution rate of drugs through an increased surface area. However, as compared to the effect on dissolution properties, decrease in particle size has comparatively little effect on the solubility of the drug substance as it does not alter the solid-state properties.Tretinoin has a very low water solubility (less than 0.2μg/ml) which can limit its utility without formulation technology.9 In addition, the
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Polymeric Matrix to Deliver Micronized Tretinoin
A number of different strategies have been proposed to achieve efficient drug delivery systems. Hydrogels are the latest advance; they are three-dimensional, cross-linked networks of water-soluble polymers commonly used in cosmetic formulations for skin care. Different polymers can be selected to formulate these hydrogels; some of the most commonly used gelling agents are carbomers, high molecular weight polymer of acrylic acid. In formulating these hydrogels product spreadability for correct dosage transfer to the target site, ease of application, extrudability from the proposed packaging, and most importantly consumer preference, must be considered.17
The adhesive capacity in dermal administration is important to ensure retention at the site of application, and active ingredient-release key for the product to exert its action either at the skin surface or within deeper layers.18 Recently, a polymeric honeycomb matrix (using carbomer cross-linked polymers, carbomer copolymer type B and homopolymer type A), which helps structure the active drug and provide a uniform distribution of both active and moisturizing/ hydrating ingredients (sodium hyaluronate, soluble collagen, glycerin) at the surface of the skin, has been deployed for the delivery of micronized tretinoin (Figure 1). The formulation also contains small amounts of mineral oil. Mineral oils are used in skin care products due to their excellent skin tolerance, as well as their antimitotic and cleansing properties and the broad viscosity options they provide. Mineral oils are not percutaneously absorbed and with an absence of dermal uptake do not become systemically available;19 at low concentrations they exhibit no comedogenicity potential.20 The concomitant use of moisturizers and humectants can enhance efficacy, alleviate dryness, and improved skin comfort. Sodium hyaluronate is a powerful humectant that attracts and holds onto water, is smaller than hyaluronic acid, and able to penetrate more freely into the deeper layers of the skin. Unlike some moisturizers, sodium hyaluronate doesn’t leave a “greasy†feel to the skin. Collagen, too, is an important component for cosmetic formulation, where it is an effective natural humectant with high substantivity. Glycerin has been shown to have a number of additional benefits beyond increasing the hydration of the stratum corneum (SC) structural elements. It prevents SC phase transition, is keratolytic, influences the protective function of the skin against irritation and penetration of substances through the SC, plasticizes the SC, reduces tissue scattering, stabilizes skin collagen, and accelerates the healing process.This polymeric matrix and vehicle lotion formulation provide
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Clinical Benefits of Micronized Tretinoin Lotion in a Polymeric Matrix
Efficacy Retinoids are the foundation of acne treatment because they have been shown to reduce visible lesions and also inhibit the development of microcomedones and new lesions. However, evidence suggests they are under-used in acne. Many physicians believe their utility is primarily restricted to treating comedonal acne; and concerns exist about cutaneous irritation, including peeling, erythema, and dryness that have limited use.17 A key aspect of acne management has been the ongoing evolution of optimal topical formulations using innovation delivery solutions that help minimize irritation, without compromising efficacy.Recently, phase 3 data with tretinoin 0.05% lotion encapsulated within a polymeric matrix were published.22 Tretinoin 0.05% lotion resulted in statistically significant reductions in both inflammatory and noninflammatory lesion reductions compared
to vehicle as early as week 8 and week 4, respectively. Mean percentage change (LS mean) from baseline to week 12 in inflammatory lesion counts was 52.1% versus 41.0% with vehicle (P less than .001, Figure 7), and in noninflammatory lesion counts 46.1% versus 29.9% with vehicle (P less than .001).Although there are currently no direct comparative studies with other tretinoin formulations, a phase 3 study with micronized tretinoin 0.05% aqueous gel reported a reduction in inflammatory lesions of 36% by week 12 (P less than 0.001 versus vehicle).23 A comparative study of this micronized tretinoin 0.05% gel and tretinoin 0.1% microsphere gel failed to show non-inferiority, although numerically the reduction in inflammatory lesions was greater with the higher concentration formulation of tretinoin.24 Safety The potential to cause irritation has been a major concern with tretinoin, and other retinoids; it appears to be dose-dependent. Micronized tretinoin 0.05% lotion in a novel polymeric matrix was very well tolerated, with a low incidence of dryness, pain (including stinging, burning, or pain), and erythema of 4%, 3%, and 1%, respectively (Figure 8). The same concentration of tretinoin (0.5%) formulated in an aqueous gel, of a similar concentration (0.04%) formulated in a microsphere reported higher incidences of skin irritation (16%, 8% and 7%, and 12%, 10%, and 6%, respectively) in two separate studies.23 A higher concentration of tretinoin (0.1%) formulated in a microsphere reported dry skin, skin burning, and erythema in 30%, 15%, and 18% of patients.
CONCLUDING REMARKS
The use of retinoids in the treatment of acne is well-established. However, efficacy in inflammatory lesions and local irritation have limited use. A number of formulation advances have been deployed to address these limitations. The most recent is the introduction of a novel polymeric matrix containing micronized tretinoin (tretinoin 0.05% lotion) and a number of formulation advances, including emulsifying agents and mineral oil. Efficacy against inflammatory lesions appears much greater than that reported previously, and tolerability better.
DISCLOSURES
Dr. Kircik has received compensation from JDD for his editorial support and has served either as an investigator, speaker, consultant, or advisory board member for Ortho Dermatologics. Dr. Draelos is a researcher for Ortho Dermatologics. Dr. Berson is consultant/adviser for Allergan, Galderma, Ortho Dermatologics, Almirall, Ferndale, Johnson & Johnson, L’Oreal, Aclaris, P&G, Dermira, Sienna, Revance, and Sonoma.
ACKNOWLEDGMENT
This research was supported by a grant from Ortho Dermatologics.
REFERENCES
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- Kaity S, Maiti S, Ghosh AK, et al. Microsponges: A novel strategy for drug delivery. J Adv Pharm Technol Res 2010;1(3):283-290.
- Brand B, Gilbert R, Baker MD, et al. Cumulative irritancy comparison of adapalene gel 0.1% versus other retinoid products when applied in combination with topical antimicrobial agents. J Am Acad Dermatol 2003;49(3 Suppl):S227-S232.
- Martin B, Meunier C, Montels D, et al. Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in the presence and in absence of visible light and ultraviolet radiation. Br J Dermatol 1998;139(suppl 52):8-11.
- Nyirady J, Lucas C, Yusuf M, et al. The stability of tretinoin in tretinoin gel microsphere 0.1%. Cutis 2002;70:295-298.
- Nighland M, Yusuf M, Wisniewshi S, et al. The effect of simulated solar UV irradiation on tretinoin in tretinoin gel microsphere 0.1% and tretinoin gel 0.025%. Cutis 2006;77 (5):313-316.
- Pariser D, Bucko A, Fried R, et al. The effect of simulated solar UV irradiation on tretinoin in tretinoin gel microsphere 0.1% and tretinoin gel 0.025%. J Drugs Dermatol 2010;9(7):805–813.
- Tabbakhian M, Sharifian A, Shatalebi MA. Preparation and in vitro characterization of tretinoin-containing microspheres suited for dermatological preparations. Res Pharma Sci 2008;3(2):31-40.
- Szuts EZ, Harosi FI. Solubility of retinoids in water. Arch Biochem Biophys 1991;287(2):297-304.
- Toll R, Jacobi IJ, Richter H, et al. Penetration profile of microspheres in follicular targeting of hair follicles. J Invest Dermatol 2004;123(1):168-176.
- Otberg N, Richter H, Schaefer H, et al. Variations of hair follicle size and distribution in different body sites. J Invest Dermatol 2004;122(1):14-19.
- Torok HM, Pillai R. Safety and efficacy of micronized tretinoin gel (0.05%) in treating adolescent acne. J Drugs Dermatol 2011;10(6):647-652.
- Brisaert MG, Everaerts I, Plaizier-Vercammen JA. Chemical stability of tretinoin in dermatological preparation. Pharm Acta Helv 1995;70:161–166.
- Brisaert M, Plaizier-Vercammen J. Investigation on the photostability of a tretinoin lotion and stabilization with additives. Int J Pharm 2000;199(1):49–57.
- Tashtoush BM, Jacobson EL, Jacobson MK. UVA is the major contributor to the photodegradation of tretinoin and isotretinoin: implications for development of improved pharmaceutical formulations. Int J Pharm 2008;352(1-2): 123–128.
- Del Rosso JQ, Harper J, Pillai R, et al. Tretinoin photostability: comparison of micronized tretinoin (0.05%) gel and tretinoin (0.025%) gel following exposure to ultraviolet A light. J Clin Aesthet Dermatol 2012;5(1):27-29.
- Garg A, Aggarwal D, Garg S, et al. Spreading of semisolid formulations an update. Pharm Technol 2002;26(9):84-105.
- Parente ME, Ochoa Andrade A, Ares Gm, et al. Bioadhesive hydrogels for cosmetic applications. Int J Cosmet Sci 2015;37(5):511-518.
- Petry T, Bury D, Fautz R, et al. Review of data on the dermal penetration of mineral oil and waxes used in cosmetic applications. Toxicol Lett 2017;280:70-78.
- Rawlings AV, Lombard KJ. A review on the extensive skin benefits of mineral oil. J Cosmet Sci 2012;34(6):511-518.
- Verma J, Jain A, Hurkat P, et al. Transfollicular drug delivery: current perspectives. Research and Reports in Transdermal Drug Delivery 2016;5:1-17.
- Tyring SK, Kircik L, Pariser DM, et al. Novel Tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: Assessment of efficacy and safety in patients aged 9 years and older. J Drugs Dermatol 2018;17(10):602-609.
- Webster G, Cargill I, Quiring J, et al. A combined analysis of 2 randomized clinical studies of tretinoin gel 0.05% for the treatment of acne. Cutis 2009;83:146-154.
- Bucks DAW, Pillai RS, McCall-Perez F. Advances in formulation technologies: creating hiughly effective and well-tolerated topical dermatologicals. Skin&Aging 2010 (Suppl):4-6.
AUTHOR CORRESPONDENCE
Leon H. Kircik MD wedoderm@yahoo.com