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11cu.nyirady
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 acnesbenzoyl peroxide topical gel and exposed tofluorescent 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 microsphere0 . 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
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vulgaris. Pediatr Dermatol. 1997;14:480-488.
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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-
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benzoyl peroxide topical gel and subjected to
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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
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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
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Dermatological, Ortho-McNeil Pharmaceutical, Inc; 1999.
Zusammenfassung der Merkmale des ArzneimittelsDie Therapie sollte so früh wie möglich inner-halb der ersten zwei Tage nach Auftreten derJede Hartkapsel enthält 98,5 mg Oseltami-13 Jahren beträgt die empfohlene orale Do-virphosphat, entsprechend 75 mg Oseltami-sis 75 mg Oseltamivir zweimal täglich überFür Kinder ab einem Jahr oder älter istTamiflu Suspension zum Einnehmen erhält-
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