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Jebmh.com Original Research Article
J. Evid. Based Med. Healthc., pISSN- 2349-2562, eISSN- 2349-2570/ Vol. 4/Issue 90/Nov. 20, 2017 Page 5355
EFFICACY AND TOLERABILITY OF BIOINOVATIVE ADAPALENE (MICRONISED) 0.1% PLUS
BENZOYL PEROXIDE (MICROENCAPSULATED) 2.5% IN ACNE MANAGEMENT
Rajendra Kharkar1, Dhammraj Borade2, Varsha Narayanan3
1Consultant Dermatologist, Dr. Kharkar Skin Clinic, Mumbai, Maharashtra, India.
2Medical Advisor, Department of Medical and Scientific Affairs, Wockhardt Limited, BKC, Mumbai, Maharashtra, India.
3Head, Department of Medical and Scientific Affairs, Wockhardt Limited, BKC, Mumbai, Maharashtra, India.
ABSTRACT
BACKGROUND
Acne vulgaris is a universal skin disease affecting both genders. Acne affects more than 85% of the teenagers as well as some
adults and persists in large number of people in their 20s and 30s age. A single-center clinic-based study from a teaching
hospital in India reported prevalence of acne among boys and girls between 12-17 years of age as 50.6% and 38.13%,
respectively. Combination therapy is an effective approach in the management of acne as it can simultaneously act on several
pathogenic mechanisms. The current (2016) European Dermatology Forum (EDF) guidelines recommend combination therapy
for all grades of acne as initial treatment.
The aim of the study is to evaluate efficacy, safety and patient satisfaction of a bioinnovative fixed-dose combination of
adapalene (micronised) 0.1% plus benzoyl peroxide (microencapsulated) 2.5% gel in the treatment of acne.
MATERIALS AND METHODS
In this prospective survey, acne patients treated with adapalene (micronised) 0.1% plus benzoyl peroxide (microencapsulated)
2.5% for four weeks were enrolled. Grade of acne, investigator global assessment and patient satisfaction scores were noted
at baseline, week 2 and week 4. Safety was assessed by recording adverse events and incidence of dryness, erythema or
irritation. Global adverse event score was calculated by adding the number of adverse events at week 2 and 4.
RESULTS
A total of 412 patients with mean duration of acne was 6.98 (5.81) months were enrolled. Number of patients with grade 3 or
4 acne reduced from 202 (49%) at baseline to 73 (17.7%) at week 2 and 31 (7.5%) at week 4, whereas number of patients
with grade 1 acne increased from 27 (6.6%) at baseline to 155 (37.6%) after 2 weeks and 277 (67.2%) at 4 weeks (p=0.001,
both at 2 and 4 weeks). Number of patients with severe acne reduced from 47 (11.4%) at baseline to 17 (4.1%) after week 2
and 8 (1.9%) after 4 weeks. The improvement in investigator global assessment after treatment at 2 and 4 weeks was
statistically significant (p=0.001). After 4 weeks of treatment, 374 (95.6%) patients were either satisfied or more than satisfied.
Mean global adverse event score reduced from 2.35 (±2.27) at week 2 to 1.68 (±1.88) after 4 weeks with 28.5% in mean
global adverse event score (p=0.001).
CONCLUSION
Technologically-enhanced formulation of adapalene (micronised) 0.1% plus benzoyl peroxide (microencapsulated) 2.5% is
significantly effective and very well tolerated in patients with acne.
KEYWORDS
Acne, Tolerability, Safety.
HOW TO CITE THIS ARTICLE: Kharkar R, Borade D, Narayanan V. Efficacy and tolerability of bioinovative adapalene
(micronised) 0.1% plus benzoyl peroxide (microencapsulated) 2.5% in acne management. J. Evid. Based Med. Healthc. 2017;
4(90), 5355-5359. DOI: 10.18410/jebmh/2017/1071
BACKGROUND
Acne vulgaris is a universal skin disease affecting both
genders. Acne affects more than 85% of the teenagers as
well as some adults1 and persists in large number of people
in their 20s and 30s age.2 A single-center clinic-based study
from a teaching hospital in India reported prevalence of acne
among boys and girls between 12-17 years of age as 50.6%
and 38.13%, respectively.3 Combination therapy is an
effective approach in the management of acne as it can
simultaneously act on several pathogenic mechanisms. The
current (2016) European Dermatology Forum (EDF)
guidelines4 recommend combination therapy for all grades
of acne as initial treatment. In severe cases, the combination
therapy is recommended along with systemic antibiotics.
Since adapalene gel 0.1% causes significantly less irritation
compared to tretinoin cream 0.025% or tretinoin
microsphere gel 0.1%.5 It is one of the preferred topical
Financial or Other, Competing Interest: None.
Submission 02-11-2017, Peer Review 10-11-2017,
Acceptance 13-11-2017, Published 15-11-2017.
Corresponding Author:
Dr. Dhammraj Borade,
Medical Advisor, Department of Medical and Scientific Affairs,
Wockhardt Limited, BKC, Mumbai, Maharashtra, India.
E-mail: dborade@wockhardt.com
DOI: 10.18410/jebmh/2017/1071
Jebmh.com Original Research Article
J. Evid. Based Med. Healthc., pISSN- 2349-2562, eISSN- 2349-2570/ Vol. 4/Issue 90/Nov. 20, 2017 Page 5356
retinoids in the treatment of acne. Adapalene is the only
retinoid, which shows compatibility when combined with
Benzoyl Peroxide (BPO).6 Fixed-dose combination of
adapalene with BPO is first line treatment of acne vulgaris.
Adapalene 0.1% plus 2.5% BPO combination is only
approved by DCGI.7 In moderate acne, combination therapy
has shown significantly higher success rates with faster
onset of action compared individual monotherapy and also
significantly greater reductions in total, inflammatory and
non-inflammatory lesion counts. Although, gel is generally
well tolerated, cutaneous tolerability,8 especially erythema,
dryness and scaling remain the most common adverse
events.9 Irritation with topical therapies may result in
reduced adherence and discontinuation of therapy.10 In
order to improve the tolerability and acceptance,
technological advancements have been done during
formulation development. Microsphere formulation of BPO
results in consistent delivery and is associated with improved
tolerability and very low chance of irritation.10
Adapalene (micronised) 0.1% benzoyl peroxide
(microencapsulated) 2.5% is prepared with improvised
technology. Bio-adhesive polymer in this product enables
adhesion of aqueous suspension to the skin. Benzoyl
peroxide present in encapsulated form ensures its stability,
penetration and sustained release over time and also
prevents the oxidation of adapalene. The technology helps
to reduce the particle size significantly. The size of
micronised adapalene is much smaller than other
formulations in the market.11 The 10% formulation retains
nearly 95% of the BPO over 30 days at 42˚C, whereas the
other commonly used formulation loses over 40% of the BPO
under identical conditions.11 Release of BPO is smoother and
penetration is enhanced due to much smaller particle size
(~0.6 micron) compared to average particle size of free BPO
(~500 micron). The formulation ensures enhanced longevity
on the skin and better deposition from a rinse-off. An in-vivo
trial in human volunteers revealed that the technologically-
advanced formulation releases benzoyl peroxide onto the
skin more slowly than free BPO.11 Understanding opinions of
the patients who have used this product will be useful to
understand, if these benefits are seen in real life settings.
Objective- The objective of this study was to evaluate
efficacy, safety and patient satisfaction of adapalene
(micronised) 0.1% plus benzoyl peroxide
(microencapsulated) 2.5% gel in the treatment of acne.
MATERIALS AND METHODS
In this prospective survey, acne patients treated with
adapalene (micronised) 0.1% plus benzoyl peroxide
(microencapsulated) 2.5% gel were enrolled. Duration of
acne and personal history regarding diet, smoking, face
wash, use of cosmetics, hair oils, presence of dandruff,
medication history and family history was recorded. In
female patients, use of oral contraceptives or hormone
replacement treatment, history of polycystic ovarian disease
or menstrual disorder, if any and relevant obstetric history
was recorded. Grade of acne, investigator global assessment
and patient satisfaction scores were noted at baseline, week
2 and week 4. Acne grading was done into four grades.
Grade 1- Comedones, occasional papules; Grade 2- Papules,
comedones, few pustules; Grade 3- Predominant pustules, a
few nodules and Grade 4- Mainly cysts, abscesses,
widespread scarring.12 Investigator’s Global Assessment
(IGA) of acne severity was performed on 5-point scale 0-
‘Clear’ (residual hyperpigmentation and erythema maybe
present); 1- ‘Almost clear’ (a few scattered comedones and
a few small papules); 2- ‘Mild’ (easily recognisable; less than
half the face is involved, some comedones and some papules
and pustules); 3- ‘Moderate’ (more than half of the face is
involved; many comedones, papules and pustules. Only one
nodule maybe present) and 4- ‘Severe’ (entire face is
involved, covered with comedones, numerous papules and
pustules, and few nodules and cysts).13
Patient Satisfaction (PS) Scoring was done on 3-point
scale; “more than satisfied” “satisfied” and “not satisfied.”
Safety was assessed by recording dryness, erythema or
irritation with the use of study medication. Severity of
adverse event was classified as mild, moderate or severe.
Global adverse event score was calculated by adding the
number of adverse events at week 2 and 4.
Statistical Analysis- Categorical data are presented as
number and percentage, whereas continuous data are
presented as mean and standard deviation. Change in
severity of acne grading and investigator’s global
assessment was assessed by Chi-square test. Change in
mean global adverse event score from week 2 to week 4 was
assessed by Student’s t-test.
RESULTS
A total of 412 patients participated in this study. Mean
duration of acne was 6.98 (±5.81) months with range
between 1 to 36 months. A total of 204 (49.5%) patients
had history of high carbohydrate/sugar consumption in diet,
whereas 195 (47.3%) patients reported presence of
dandruff. History of smoking was present in 61 (14.8%)
patients, family history of acne and PCOD/any other
menstrual disorder was present in 40 (9.7%) and 49
(11.9%) patients, respectively. Consumption of oral
contraceptives or Hormone Replacement Therapy (HRT) was
reported by 23 (5.6%) patients (Table 1).
Personal History
N (%)
High carbohydrate/sugar or lactose diet
204 (49.5%)
Smoking
61 (14.8%)
Presence of dandruff
195 (47.3%)
Currently on any medication
60 (14.6%)
Family history
40 (9.7%)
Any systemic complaints
11 (2.7%)
Using oral contraceptives or HRT
23 (5.6%)
Diagnosed with PCOD or
any menstrual disorder
49 (11.9%)
Table 1. Personal History (n=412)
Jebmh.com Original Research Article
J. Evid. Based Med. Healthc., pISSN- 2349-2562, eISSN- 2349-2570/ Vol. 4/Issue 90/Nov. 20, 2017 Page 5357
Baseline
N (%)
2 Weeks
N (%)
4 Weeks
N (%)
Grade 1
27 (6.6%)
155 (37.6%)
277 (67.2%)
Grade 2
183 (44.4%)
184 (44.7%)
104 (25.3%)
Grade 3
165 (40%)
56 (13.6%)
24 (5.8%)
Grade 4
37 (9%)
17 (4.1%)
7 (1.7%)
Table 2. Changes in Proportion of Cases with
Severity of Acne after the Treatment (n=412)
At baseline, 202 (49%) patients had grade 3 or 4 acne.
After 2 and 4 weeks of treatment, the number of patients
with grade 3 or 4 acne reduced to 73 (17.7%) and 31
(7.5%), respectively (Table 2). Number of patients with
grade 1 acne increased from 27 (6.6%) at baseline to 155
(37.6%) after 2 weeks and 277 (67.2%) after 4 weeks. This
change in severity of acne grade was statistically significant
(Table 2; p=0.001).
Baseline
N (%)
2 Weeks
N (%)
4 Weeks
N (%)
Clear/almost
clear
28 (6.8%)
151 (36.7%)
283 (68.7%)
Mild
161 (39.1%)
183 (44.4%)
96 (23.3%)
Moderate
176 (42.7%)
61 (14.8%)
25 (6.1%)
Severe
47 (11.4%)
17 (4.1%)
8 (1.9%)
Table 3. Investigator Global Assessment
After The Treatment (n=412)
Results of investigator’s global assessment after
treatment are shown in Table 3. At baseline, numbers of
patients with clear/almost clear, acne were only 28 (6.8%)
patients. Number of patients with mild, moderate and severe
acne at baseline were 161 (39.1%), 176 (42.7%) and 47
(11.4%), respectively. After 2 weeks of treatment, number
of patients with severe acne reduced to 17 (4.1%) and 8
(1.9%) after 4 weeks of treatment. After 4 weeks of
treatment, lesions of acne were clear/almost clear in 283
(68.7%) patients (Table 3). The improvement in investigator
global assessment after treatment at 2 and 4 weeks was
statistically significant (p=0.001). Responses of patient
satisfaction ratings are shown in Figure 1 and 2.
Figure 1. Patient Satisfaction After
2 Weeks of Treatment (n=392)
Figure 2. Patient Satisfaction After
4 Weeks of Treatment (n=392)
A total of 343 (87.5%) patients were either satisfied or
more than satisfied after 2 weeks of treatment. After 4
weeks of treatment, 374 (95.6%) patients were either
satisfied or more than satisfied. Only 4.6% patients were not
satisfied with the response after 4 weeks (Figure 2).
Table 4 shows number and percentages of patients with
dryness, erythema and irritation after 2 and 4 weeks of
treatment. A total of 157 (38.1%) and 203 (49.2%) patients
did not have dryness after 2 and 4 weeks, respectively.
Number of patients without erythema at 2 weeks and 4
weeks were 214 (51.9%) and 235 (57%), respectively.
Numbers of patients without irritation at 2 and 4 weeks were
210 (51%) and 242 (58.7%), respectively.
Dryness
Erythema
Irritation
2 Weeks
N (%)
4 Weeks
N (%)
2 Weeks
N (%)
4 Weeks
N (%)
2 Weeks
N (%)
4 Weeks
N (%)
None
157 (38.1%)
203 (49.2%)
214 (51.9%)
235 (57.1%)
210 (51%)
242 (58.7%)
Mild
145 (35.2%)
156 (37.9%)
120 (29.2%)
147 (35.7%)
105 (25.5%)
124 (30.1%)
Moderate
100 (24.3%)
46 (11.2%)
70 (17%)
29 (7%)
85 (20.6%)
44 (10.7%)
Severe
10 (2.4%)
7 (1.7%)
8 (1.9%)
1 (0.2%)
12 (2.9%)
2 (0.5%)
Table 4. Proportion of Cases with Dryness After the Treatment (n=412)
Figure 3. Changes in Mean Global Adverse
Event Score Among Study Cases (n=412)
Mean global adverse event score at week 2 was 2.35
(±2.27), which reduced to 1.68 (±1.88) after 4 weeks. This
change (28.5%) in mean global adverse event score was
statistically significant (Figure 3; p=0.001).
DISCUSSION
Acne is a common dermatological disorder seen in clinical
practice. Several factors including diet, smoking, genetics
and ethnicity have role in the development of acne.2 In our
study, almost half of the participants reported consumption
Jebmh.com Original Research Article
J. Evid. Based Med. Healthc., pISSN- 2349-2562, eISSN- 2349-2570/ Vol. 4/Issue 90/Nov. 20, 2017 Page 5358
of high carbohydrate diet. Considering this association,
patients are advised to reduce high carbohydrate diet.
Family history is a risk factor for early and more severe form
of acne.2 In our study, close to 10% patients had positive
family history and had severe acne in 11.4% according to
Investigator’s Global Assessment. It would be worthwhile to
see, if all the severe cases had positive family history. Role
of smoking in acne is controversial.2 In our study, 14.8%
patients reported history of smoking.
Topical retinoid is the first line therapy for mild
comedonal form of acne, while for papular/pustular form of
mild acne, its combination with topical antimicrobial agent is
recommended as first choice of therapy. In moderate-to-
severe acne, topical retinoid plus BPO plays an important
role.14
Combination therapy of topical adapalene/BPO or with
antibiotics is preferred in mild-to-moderate acne.
Several guidelines recommend use of topical retinoid
plus BPO in the management of acne.4,15-17 The combination
is recommended as initial therapy in the management of
mild and moderate acne,4,16,17 whereas in severe cases, it is
recommended along with oral antibiotics.4,16 Being directly
toxic to the P. acne, BPO offers advantages over antibiotics
in the treatment of acne vulgaris. It is not associated with
development of P. acne resistance18 and also has an ability
to reduce resistant P. acne strains.19 Alteration of
microenvironment by BPO can decrease attachment of P.
acne to the follicular lining, which helps to reduce biofilm
formation.20
Efficacy of adapalene plus BPO in the treatment of acne
vulgaris is very well known.13,14,21,22 Combination of
adapalene- BPO has been shown to work better in patients
with more number of lesions at the start of therapy.23 A
recently published study showed topical long-term
treatment (6 months) with combination of adapalene 0.1%
plus benzoyl peroxide 2.5% reduces risk of atrophic scars
and results in improvement of the global severity of
scarring.24
Even in the mild acne, topical retinoid plus BPO is one
of the recommended initial therapies by Indian guideline on
acne management.25 In line with the published evidence, we
also observed similar results. Compared to baseline, number
of patients with moderate and severe acne reduced
significantly over time in our study. Investigator’s global
assessment was also consistent. According to the
investigator global assessment, the response after treatment
was statistically significant. Efficacy is not the major concern
with adapalene plus BPO combination.
Local irritancy is a common adverse event with topical
retinoids and combination of adapalene plus BPO. Erythema,
dryness, peeling/scaling and burning are the most common
local adverse events with these formulations.9,26 Irritation
caused by adapalene gel 0.1% is lesser as compared to
other topical retinoids, i.e. tretinoin cream 0.025% or
tretinoin microsphere gel 0.1%.5 Topical adverse events in
the form of dryness, erythema and irritation may reduce
acceptance and compliance in some patients. Consistent
efforts are done to reduce the incidence and severity of
these adverse events. One of the measures is to improvise
the product formulation. Technology used in the
manufacturing of gel provides advantages of reduced
particle size, adhesion of aqueous suspension to the skin,
stability, penetration and sustained release over time.11
These advantages might improve the tolerability of the
formulation. In order to understand, the profile of local
adverse events with technology-enhanced formulation
(micronization and microencapsulation), we recorded
severity of these adverse events at 2 and 4 weeks and found
no dryness, erythema and irritation in 49.2%, 57.1% and
58.7% patients after 4 weeks of treatment. Overall, dryness,
erythema and irritation were absent or mild in nature among
87.1%, 92.8% and 88.8% patients, respectively. There was
significant reduction in mean global adverse event from
week 2 to week 4. These observations confirm good safety
profile of the formulation.
Open label, non-comparative study design and
subjective evaluation are the limitations of our study.
Considering these limitations, we suggest to carefully
extrapolate our findings.
CONCLUSION
Technologically-advanced formulation of adapalene BPO
confirms efficacy in patients with acne. Importantly, adverse
events are minimised with the improvised formulation.
Considering balanced efficacy and tolerability, it may be
considered as preferred first line agent for acne treatment.
Acknowledgement
We acknowledge the contribution of Wockhardt
Dermatology marketing team under Mr. Prince Uppal for
study executional support. The authors acknowledge the
help provided by Dr. Anant Patil for writing, editing and
submission of manuscript.
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