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The Stability of Tretinoin in Tretinoin Gel Microsphere 0.1% Judit Nyirady, MD; Carmelle Lucas, PhD; Mohammed Yusuf, MS; Pamela Mignone, BA; Stephen Wisniewski, PhD Topical tretinoin is highly effective and widely used psoriasis, and photodamaged skin. When prescribed in the treatment of acne vulgaris. In studies to as a treatment for acne vulgaris, tretinoin often is determine the degree of tretinoin photo degra- used in combination with a topical antibacterial dation (isomerization), 2 tretinoin formulations, agent (ie, clindamycin, erythromycin, benzoyl tretinoin gel microsphere 0.1% and tretinoin gel peroxide) because to date, no single topical thera- 0.025%, alone or in combination with erythromycin- peutic agent is capable of ameliorating all the benzoyl peroxide topical gel, were exposed to etiologic factors of acne vulgaris.1 Present-day fluorescent light, incandescent light, or darkness treatment of acne usually centers around the topi- for up to 24 hours. Results of the investigations cal application of retinoids to reverse microcomedo revealed that after 24 hours of exposure to fluo- formation (hypercornification, hyperkeratiniza- rescent light, 98% of the initial tretinoin in the tion, and hypodesquamation of the follicular t re t i n o i n g e l m i c ro s p h e re 0 . 1 % f o r m u l a t i o n infundibulum), while antibiotics such as erythro- remained unchanged. When tretinoin gel micro- mycin or a strong oxidizing agent such as benzoyl sphere 0.1% was combined with erythromycin- peroxide is used to kill the Propionibacterium acnes benzoyl peroxide topical gel and exposed to fluorescent light, 99% and 87% of the tretinoin The effectiveness of topical tretinoin is well was recovered after 4 and 24 hours, respectively, established,1,2 though skin irritation in some indicating only a limited amount of degradation. patients3 and susceptibility to photo degradation In contrast, exposure of tretinoin gel 0.025% to under various light conditions4,5 in others have 24 hours of fluorescent light resulted in up to been reported. Combinations of tretinoin and ben-69% tretinoin degradation and up to 89% degra- zoyl peroxide were found to degrade more rapidly dation when the gel was combined with the than the tretinoin itself when exposed to actinicerythromycin-benzoyl peroxide topical gel. The (fluorescent) light because of the strong oxidative data suggest that the tretinoin gel microsphere 0 . 1 % f o r m u l a t i o n o ff e r s m a r k e d p ro t e c t i o n Tretinoin gel microsphere 0.1%, a microsponge against tretinoin photo degradation, even in the formulation, was developed with the goal of min- presence of a strong oxidizing agent such as imizing cutaneous irritation.6 This polymeric deliv- ery system, consisting of porous microspheres thatentrap active ingredients, markedly decreased the Tretinoin (all-trans-retinoic acid) is used widely incidence of noninflammatory lesions in 2 clinical in topical formulations for the treatment of trials7 and demonstrated a lower irritation profile various skin disorders, such as acne vulgaris, when compared with tretinoin cream 0.1% in ahalf-face comparative study and a 21-day cumula-tive irritation study.8 However, no literature refer- From Johnson & Johnson Consumer Products Worldwide, ences could be found that documented the degree of photo degradation (isomerization) of tretinoin in Reprints: Judit Nyirady, MD, Medical Affairs, Johnson & Johnson this particular formulation. Therefore, the objec- Consumer Products Worldwide, 199 Grandview Rd, Skillman, NJ08558-9418 (e-mail: jnyirad@cpcus.jnj.com).
tives of the present study were to study the effect of Figure 1. Light spectrum of fluorescent and incandescent lighting. Vertical dotted lines represent mercury cali-
bration peaks at 296, 303, 313, 333, 365, 405, 436, and 546 nm.
different indoor lighting conditions (fluorescent imately 4.0 g of these mixtures then were placed and incandescent lights, as well as darkness) on the into individual 5-mL plastic syringes, one for each degradation of tretinoin in tretinoin gel micro- sphere 0.1% and tretinoin gel 0.025%, with and The fluorescent light source included eight 32-W without the addition of an erythromycin-benzoyl tubular lightbulbs; the incandescent light source included four 75-W lightbulbs. Spectral comparisonof the illumination from the fluorescent and incan- Materials and Methods
descent lighting is shown in Figure 1. The spectrum Materials—Tretinoin gel microsphere 0.1% and encompasses the visible light spectrum and only min- tretinoin gel 0.025% were obtained from Ortho imal spectrum from UVA.
Dermatological, Ortho-McNeil Pharmaceutical, Inc.
Syringes were exposed to specified light conditions The erythromycin-benzoyl peroxide topical gel was (fluorescent, incandescent, or darkness) for 0, 1, 2, 4, Methods—Both tretinoin gel microsphere 0.1% After exposure to the various lighting condi- and tretinoin gel 0.025% were placed into separate tions, test samples were analyzed for tretinoin via beakers and vortexed for 2 to 3 minutes. Approxi- high-performance liquid chromatography (HPLC).
mately 4.0 g of each product then were placed into HPLC assays were conducted using a Supelcosil 5-mL plastic syringes, one for each time point. In a LC-18 (5 µm, 25-cmϫ4.6-mm column). Separation similar manner, 40.5 g of tretinoin gel microsphere was achieved with a mobile phase of acetonitrile/ 0.1% and 40.5 g of tretinoin gel 0.025% each were water/glacial acetic acid in a ratio of 800/200/0.2.
mixed with 4.5 g of the erythromycin-benzoyl per- Wavelength and flow rate were set at 353 nm and oxide topical gel in a beaker for 5 minutes. Approx- 1.8 mL/min, respectively. Column temperature and Figure 2. The percentage of
0.1% alone and when mixedwith erythromycin-benzoyl peroxide topical gel whenthe lighting condition is (A) Tretinoin gel microsphere, 0.1% ϩ erythromycin-benzoyl peroxide topical gel fluorescent, (B) incandes-cent, and (C) darkness.
injection volume were 30°C and 10 µL, respec- peaks that were barely detectable. Two similar tively. All tretinoin analyses were conducted in but slightly larger peaks also were observed after duplicate and results given as a percentage of the analysis of the 24-hour samples of tretinoin gelinitial content.
microsphere 0.1% mixed with erythromycin-benzoylperoxide topical gel and exposed to fluorescent light.
Graphic stability profiles for tretinoin gel micro- HPLC analysis of the 24-hour tretinoin gel micro- sphere 0.1% and tretinoin gel microsphere 0.1% sphere 0.1% samples exposed to fluorescent light mixed with erythromycin-benzoyl peroxide topical revealed the presence of only 2 small degradation gel and exposed to the 3 light conditions are illustrated in Figure 2. The amount of tretinoin the tretinoin in the tretinoin gel 0.025% had under- recovered from the tretinoin gel microsphere 0.1% gone degradation after 24 hours of exposure to samples at each time point was 98% of the initial fluorescent light when it was combined with amount, regardless of the lighting condition (one erythromycin-benzoyl peroxide topical gel. Sixty- exception: 97% recovery occurred at 4 hours in the nine percent of the tretinoin was degraded under the absence of light). Tretinoin in the tretinoin gel same exposure conditions in tretinoin gel 0.025% microsphere 0.1% mixed with erythromycin- alone. These results are similar to those obtained by benzoyl peroxide topical gel remained essentially unchanged after 4 hours of exposure to fluorescent Although the findings of Martin et al5 were con- light, incandescent light, or darkness (99%, 97%, firmed in the present study with the tretinoin gel and 96% of initial values, respectively). After 0.025%, degradation of tretinoin was limited in the8 hours of exposure, 94% to 95% of the initial tretinoin gel microsphere 0.1% formulation. In fact, tretinoin was recovered in the samples. After the tretinoin gel microsphere 0.1% formulation itself24 hours of exposure, 87%, 86%, and 90% of was completely stable (98% recoverable) when tretinoin remained stable in the samples exposed to exposed to fluorescent light, incandescent light, or fluorescent light, incandescent light, or darkness.
darkness over a period of 24 hours. When combined with erythromycin-benzoyl peroxide topical gel, 87% tretinoin gel 0.025%, either alone or mixed with of the initial tretinoin remained stable.
erythromycin-benzoyl peroxide topical gel and The tretinoin gel microsphere 0.1% formulation exposed to fluorescent light, revealed the presence not only demonstrated a lower irritation profile than of multiple large peaks representing a variety of tretinoin cream 0.1% in clinical studies8 but also pro- degradation products. The degradation products vides a high degree of protection against tretinoin were more numerous in the tretinoin gel 0.025% photo degradation, even in the presence of benzoyl mixed with erythromycin-benzoyl peroxide topical peroxide and erythromycin. These important findings gel. Exposure to fluorescent light for 24 hours should be taken into consideration when tretinoin resulted in a 69% degradation of tretinoin in combination therapy is chosen in the clinics.
tretinoin gel 0.025% and an 89% degradation oftretinoin when combined with erythromycin- Acknowledgment—The authors would like to acknowledge the technical assistance of Dr. RobertDiener, Ms. Kate Huddleston, and Mr. Jeffrey Pote.
Comment and Conclusion
Various formulations of tretinoin (gel, cream, liquid)
REFERENCES
are used extensively to reduce hyperkeratinization 1. Weiss JS. Current options for the topical treatment of acne and to unplug pilosebaceous follicles, the initial vulgaris. Pediatr Dermatol. 1997;14:480-488.
lesion of acne vulgaris. These preparations have 2. White GM. Acne therapy. In: James WD, Cockerell CJ, been reported to be unstable on the skin under Dzubow LM, et al, eds. Advances in Dermatology. Vol 14. St bright artificial light or sunlight.1,4 Furthermore, Martin et al5 have reported that as much as 95% of 3. Leyden JJ. Topical treatment of acne vulgaris: retinoids and the initial quantity of tretinoin in tretinoin gel cutaneous irritation. J Am Acad Dermatol. 1998;38:S1-S4.
0.025% degraded when mixed with erythromycin- 4. Brisaert M, Plaizier-Vercammen J. Investigation on the benzoyl peroxide topical gel and subjected to photostability of a tretinoin lotion and stabilization with additives. Int J Pharm. 2000;199:49-57.
The present investigation examined the stability 5. Martin B, Meunier C, Montels D, et al. Chemical stability of tretinoin in the microsponge formulation and of adapalene and tretinoin when combined with benzoyl compared it with the stability of tretinoin in the peroxide in presence and in absence of visible light and ultra- tretinoin gel 0.025% formulation under various violet radiation. Br J Dermatol. 1998;139(suppl 52):8-11.
indoor lighting conditions. The spectrum of indoor 6. Nacht S, Katz M. The microsponge: a novel topical pro- lights covered the visible light spectrum and included grammable delivery system. In: Osborne DW, Amann AH, only minimal UVA radiation. The effect of solar eds. Topical Drug Delivery Formulations. New York, NY: radiation on tretinoin in the tretinoin gel micro- sphere 0.1% formulation also has been completed 7. Webster GF. Topical tretinoin in acne therapy. J Am Acad recently, and results will be published separately.
Results from the present investigation revealed 8. Retin-A Micro [package insert]. Skillman, NJ: Ortho that under the test conditions of the study, 89% of Dermatological, Ortho-McNeil Pharmaceutical, Inc; 1999.

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