Materials Technology

Advanced Performance Materials

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Design and development of solid lipid

nanoparticles of tazarotene for the treatment of
psoriasis and acne: a quality by design approach

Sanjay Sharma , Abhishek Kanugo & Juilee Gaikwad

To cite this article: Sanjay Sharma , Abhishek Kanugo & Juilee Gaikwad (2021): Design and
development of solid lipid nanoparticles of tazarotene for the treatment of psoriasis and acne: a
quality by design approach, Materials Technology, DOI: 10.1080/10667857.2021.1873637

To link to this article: https://doi.org/10.1080/10667857.2021.1873637

Published online: 15 Jan 2021.

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MATERIALS TECHNOLOGY
https://doi.org/10.1080/10667857.2021.1873637

RESEARCH ARTICLE

Design and development of solid lipid nanoparticles of tazarotene for the

treatment of psoriasis and acne: a quality by design approach
Sanjay Sharma , Abhishek Kanugo and Juilee Gaikwad
SVKM NMIMS School of Pharmacy and Technology Management, Shirpur, India

ABSTRACT ARTICLE HISTORY

Tazarotene is a third-generation retinoid applied topically for the treatment of psoriasis and Received 2 December 2020
acne. But its applications are limited due to its poor solubility and bioavailability. The current Accepted 30 December 2020
investigation aimed at the development of solid lipid nanoparticles (SLN) of Tazarotene for KEYWORDS
effective topical delivery. Depending on the solubility, stability, and compatibility lipids and Key-words: Tazarotene; solid
surfactants were selected and further optimised. SLN of Tazarotene was developed by hot- lipid nanoparticles; psoriasis;
homogenisation followed by probe sonication method. Preformulation studies were carried entrapment efficiency;
out and compatibility was confirmed with FTIR. The design of the expert, Box Behnken model particle size; zeta potential
was implemented and the surface response curve was plotted. Glyceryl monostearate was
found to be the best lipid and a combination of tween-span as a surfactant for SLNs. The
entrapment efficiency was found as 59% and the particle size of 470 nm was reported. The
optimised batch showed the zeta potential of −10.3 Mv with a drug release of 59% to 77% after
6 h.

Introduction transdermal formulations have shown undesired

Retinoids are the mostly used topically for the
treatment of non-inflammatory and inflammatory
acne. Adapalene, Tazarotene, and Tretinoin are the
most widely used topical retinoids approved by the
Food and Drug Administration (FDA) [1,2]. The
pharmacokinetic parameters of TZR reflected the
safe and effective topical therapy for plaque psor­
iasis [3].
Solid lipid nanoparticles (SLNs) have gain lots of
attention of researchers since the last decade due to
the applicability of conveying lipophilic and hydro­
philic active ingredients. These nanoparticles are
significantly showed high degree of
a biocompatibility, biodegradability, nontoxicity,
and physicochemical characteristics of lipids,
hence considered for overall routes of drug admin­
istration. These nanoparticles also exhibited great
surface to volume ratio, high loading efficiency,
nanosize and facilitates the production of pharma­
ceutical products [4]. These are mainly composed
of solid lipids and stabilises with surfactants inside
the aqueous dispersion. SLNs are generally consid­
ered as the submicron colloidal carrier with an
achievable particle size of 50 to 1000 nm. These
are rendering as solid at room temperature as well
as inside the body [5].
SLNs are the most widely used techniques for
enhancing the solubility and thereby bioavailability
of poorly soluble active ingredients due to the
digestion of lipids [6,7]. The topical delivery or
adverse reactions [8]. To overcome these limita­
tions, colloidal drug delivery was introduced
which gains attention recently for promoting drug
absorption and delivering at targeted sites [9,10].
SLNs are a colloidal carrier system found to be best
suitable due to their wide merits like promoting
hydration of skin, facilitates the release of drugs,
skin occlusion, the blocking action of UV rays,
achievable drug targeting, improved stability
[9,11,12]. Moreover, SLNs formulations are benefi­
cial as it avoids the use of organic solvents, ease of
scale-up, and delivered in a controlled manner
[13,14].
Quality by Design (QbD) is a systematic techni­
que for the build-up of product and operation
control. The principal involved in the QbD for
the advancementinvolves the preferred outcomes
with a superior thoughtful process and preparation
variable [15].
TZR is applied topically as cream or gel and
useful for the treatment of acne, psoriasis, sun­
burned skin. Some of the adverse effects associated
with TZR gel-like redness, burning, itching, dry­
ness, skin discolouration, rash blistering, and peel­
ing at the site of application. TZR having short
local bioavailability (14%) accompanied by the
above adverse effects [16,17]. The study aimed to
formulate stable TZR-loaded SLNs and further
explores the possibility of using these novel formu­
lations to cure psoriasis and acne.

CONTACT Abhishek Kanugo abhi.kanugo09@gmail.com SVKM NMIMS School of Pharmacy and Technology Management, Shirpur 425405, India
© 2021 Informa UK Limited, trading as Taylor & Francis Group
2 S. SHARMA ET AL.
Materials and method
Materials
Tazarotene was received as a gift sample from Sun
Pharma, Vadodara, Gujrat. HPLC grade methanol
was purchased from Merck, Mumbai. All other
reagents utilised are of analytical grades.
Method
Selection of lipid
The lipid was selected in which the highest amount
of active ingredient gets solubilised. The solubility
of Tazarotine was determined in several lipids like
glyceryl monostearate, glyceryl caprylate, glyceryl
behenate and soy lecithin. An accurately weighed
quantity of Tazarotine was transferred to melted
lipids with continuous stirring. Moreover, an excess
amount of lipids was incorporated with heating
until a transparent solution was achieved [18].
Selection of the surfactant system
Tween 20, Tween 80, span 80, poloxamer 188, sodium
lauryl sulphate, etc., were tested for solubility and
stability of solid lipid nanoparticles and appropriate
surfactant was selected [19].
Preformulation studies
Determination of solubility
Accurately weighed about 10 mg of TZR was transferred
to each of 10 ml of the volumetric flask containing 1 ml
of solvents like distilled water, methanol, acetone, acet­
onitrile, and benzyl alcohol, respectively. The solution is
stirred and evaluated for solubility determination.
Determination of melting point of TZR
The melting point of TZR was assessed using
a microcontroller-based melting point apparatus.
Standard calibration curve of TZR
The stock solution of TZR was prepared by trans­
ferring an accurately weighed quantity of 10 mg in
100 ml of the volumetric flask containing 10 ml of
methanol. The solution was further sonicated for
about 15 min and make up the volume with dis­
tilled water. Aliquots were taken, and filter over
a membrane filter (0.45µ) and scan in the range of
200–400 nm by UV visible spectrophotometer.
Fourier transform infra-red spectroscopy (FTIR)
FTIR spectroscopic analysis was carried out
(Shimadzu IRAffinity-1S) for pure TZR using the
KBr press method. The quantity of drug equivalent
to tablet weight and other excipients in their appro­
priate proportions were mixed thoroughly and finally
compressed. The compatibility study was carried out
to check any kind of interactions among drugs with
lipids like GMS and Poloxamer at a wavelength of 500
to 4000 cm−1.
Experimental design
DOE model (Box Behnken) for TZR loaded SLN
Design-Expert®11(Stat-Ease, Inc, US) software
intended for the generation of the design matrix to
find out an optimised formulation batch. The opera­
tion of optimisation by full factorial design is required
so that investigation gets finalised and mathematical
models can be created. Each trial’s responses were
recorded and implemented multiple linear regression
analysis and F-statistics. The significant terms were
recognised using an appropriate model. The concen­
tration of lipid and surfactants is the independent
variables and the entrapment efficiency, percentage
of drug release is considered as dependable parameters
while utilising DOE.
The effect of lipid and concentration of surfactant
and sonication time on entrapment efficiency (EE)
and drug release (DR) can be realised via response
surface plots and contour plots generated using design
expert software. ‘’Quadratic polynomial model was
considered statistically for all the data and interrelated
concerning to correlation coefficient (r2), adjusted
correlation coefficient (adjusted r2), adequate preci­
sion and predicted correlation coefficient (predicted
r2)”. Furthermore, the 2 and 3Dimension counter and
surface response plots were analysed for the concur­
rent relationship between all the variables and
responses. An optimised formulation batch was pre­
dicted based on the explanations of mathematical and
graphical optimisation [20].
Formulation of solid lipid nanoparticles
The SLNs of TZR were developed by using hot homo­
genisation and later with the Probe sonication
method. In the hot homogenisation method, GMS
and poloxamer were melted above their melting
point. TZR was incorporated in the melted phase
and allow dissolving it. The aqueous phase was also
heated about the same temperature of lipids and added
slowly in the lipid phase, and homogenised them at
2500 rpm at about 70°C utilising a mechanical stirrer
about 30 min. The prepared coarse oil in water emul­
sion was further sonicated by probe sonicator for
 MATERIALS TECHNOLOGY 3

another 25 min. SLNs of TZR were developed as Stability studies

Nanoemulsion which was cool and stored. The
An optimised batch was tested at different tempera­
Experimental result of the effect of lipid concentration,
tures of 4°C and 25 ± 2°C. Samples were withdrawn
surfactant concentration, and sonication time on
regularly at an interval of 15 days and subjected for
entrapment efficiency and drug release by DOE was
their drug content. Finally, entrapment efficiency was
depicted in Table 1 [21,22].
compared and reported [26]

Characterisation of SLN
Scanning electron microscopy
Entrapment efficiency
The surface morphology of SLN formulations was
Estimation of drug entrapment efficiency was deter­
observed by scanning electron microscopy. Before
mined for each batch indirectly by counting the quan­
observation, the lyophilised samples were fixed on
tity of the free TZR in the clear supernatant following
a double adhesive carbon tape, which was stuck on
centrifugation spectrophotometrically at 351 nm by
aluminium stubs and then coated with gold under
UV visible spectrophotometer [23,24]. These are cal­
an argon atmosphere. The samples were visualised
culated as
by SEM with an accelerating voltage of 8–20
Quantity of entrapped drug kV [28].
% Entrapment efficiency ¼
Total quantity of drug
� 100
HPLC analysis of TZR
TZR content was determined using the Perkin Elmer
series 200 HPLC (Shimadzu Prominence-PDA) out­
In vitro drug release fitted with Binary solvent manager by RP-HPLC [29].
A UV/Visible detector and rheodyne manual sample
It was estimated with reverse ‘’dialysis bag technique”.
injector with a 20 μL fixed loop were used. Kromasil
An amount of 2.5 mg of SLNs dispersion was trans­
C18 column (4.6 ˟100 mm, 5 μm), along with a guard
ferred in 250 ml of beaker holding saline phosphate
column was used. After mixing, the mobile phase,
buffer of pH 7.4 at 37°C, about 50 rpm. Samples were
which comprised of methanol: water (90:10, v/v), was
withdrawn at regular intervals and the drug amount
degassed. The eluent was run at a rate of 1.0 ml/min
was measured spectrophotometrically about 351 nm.
and monitored at 351 nm.
The study was performed in triplicate and average
values showed in standard deviation [25,26].
Results
Particle Size, PDI, and Zeta Potential Selection of lipid
Zeta potential is an indicator of the stability of colloi­ Depending on the highest solubility, the lipid is cho­
dal dispersion. An optimised batch was determined by sen for the formulation of SLNs. Out of them, GMS
using Malvern Zetasizer after suitable dilution with was found to be the best suitable lipid for the formula­
deionised water [27]. tion of SLN of TZR.

Table 1. Experimental result of the DOE to study TZR loaded solid lipid nanoparticle containing different concentration of lipids
surfactant and sonication time.
Factor 1 Factor 2 Factor 3 Response 1 Response 2
Batch Std Run A:Lipid Concentration B:Surfactant C:Sonication Time Entrapment Drug Release
Mg mg min % %
F1 12 1 2.5 2 10 56 71
F2 5 2 1 1.5 5 53 68
F3 8 3 4 1.5 10 57 71
F4 11 4 2.5 1 10 59 72
F5 4 5 4 2 7.5 54 76
F6 7 6 1 1.5 10 51 59
F7 3 7 1 2 7.5 48 65
F8 13 8 2.5 1.5 7.5 60 76
F9 9 9 2.5 1 5 59 69
F10 1 10 1 1 7.5 51 68
F11 10 11 2.5 2 5 63 77
F12 6 12 4 1.5 5 57 70
F13 2 13 4 1 7.5 55 71
4 S. SHARMA ET AL.

Selection of surfactant
Surfactants were selected based on the producing
SLNs of smaller particle size, polydispersity index,
stability, and safety. Out of the stated characteristics,
SLS has complied with almost all of the characteristics
except safety profile, hence not considered for the
formulation of SLNs. Individual surfactants failed to
produce the requirements of SLNs. Therefore, certain
combinations were also tested, out of them Tween 80
and Span 20 satisfactorily comply with the desired
one. Tween and Span in combined form impart stabi­
lity to the aqueous and lipid phases, respectively, [30].
Preformulation studies
Solubility studies
The solubility of TZR was checked in several solvents
and observed practically insoluble in water (reported
value 0.00075 mg/ml and log P of 5.15) and freely
soluble in methanol, acetone, acetonitrile, and benzyl
alcohol. The results indicated TZR is highly lipophilic
in nature and practically insoluble in water.
Melting point
The melting point of TZR was found at 103°C to
106°C.
Calibration curve
The standard calibration curve of TZR was carried out
using UV visible spectrophotometer (Shimadzu 1800)
and observed absorbance spectra at 351 nm. The cali­
bration graph showed linearity in the concentration
range of 8–20 µg/ml indicated to follow the Beer–
Lambert law and correlation coefficient of 0.9848.

Figure 1. Absorption spectra of TZR.

Figure 2. FTIR spectra.

 MATERIALS TECHNOLOGY 5

The absorption spectrum of TZR was depicted in
Figure 1.
Interaction study by FTIR
The spectrum of TZR was recorded by ATR showed
a sharp peak at 3672.47 owing to hydroxyl stretching,
2198.85 for C ≡ C stretching, 1716.65 for C = O,
1153.43 for C-O, 1473.62 for CH2 (Figure 2).
The physical mixture along with SLNs confirmed
the availability of all the peaks and lack of any
functional peaks in all the spectra was not recorded.
Hence, it was interpreted that formulation ingredi­
ents were compatible and not any significant physi­
cochemical interaction between drug and lipid in
the formulation.
Optimisation by DOE and Box Behnken
DOE model (Box Behnken) for TZR loaded SLN
Statistically, DOE software was used for the optimisa­
tion of designated variables using Box Behnken design
[31,32]. ‘’Selected critical quality attributes (CQAs)
such as DR and EE, the quadratic polynomial model
is the choice of the best fitted for this study”. The
recommended model was significantly proved by the
ANOVA-F test (p< 0.05) [33]. ANOVA results of the
entrapment efficiency (EE) and Drug Release (DR)
factor shown in Table 2.
ANOVA for quadratic polynomial model
The Model F-value of 10.92 and 14.72 denotes the
model is significant concerning EE and DR, respec­
tively. There is only a 3.71 for EE and 2.44% for DR
chances. p-values smaller than 0.0500 indicate model
terms are significant. In the EE case A, A2 are signifi­
cant model terms and in the case of DR case A, AC,
A2, C2 are significant model terms. From the above
data, we conclude that the model was significant.
Fit statistics
The high R2 values for Entrapment efficiency (EE) and
drug release (DR) responses characterised the greatest
fit of the polynomial quadratic model (p< 0.0500).
Moreover, the adjusted r2 and actual r2 values were
nearer to each other; therefore, we conclude that this
model used to traverse the design space which further
confirms the good fit of the same. Table 3 summarises
all the statistical data from BBD. Adeq Precision mea­
sures the signal to noise ratio. A ratio greater than 4 is
desirable. The ratio of 10.368 and 13.725 indicates an
adequate signal for EE and DR, respectively. This
model can be used to navigate the design space.
However, the simultaneous response of EE and DR
with all the variables were assessed with 3D response
surface plots and 2-D contour plots (Figures 3 and
Figures 4) Statistical report of Response 1, EE and
response 2, DR using BBD (Table 3).

Table 2. ANOVA results of the entrapment efficiency (EE) and Drug Release (DR) factor.
Source Sum of Squares df Mean Square F-value p-value
ANOVA results of the entrapment efficiency (EE) factor Model 204.83 9 22.76 10.92 0.0371 Significant
A-Lipid Conc 50.00 1 50.00 24.00 0.0163
B-Surfactant 1.13 1 1.13 0.5400 0.5157
C-Sonication Time 10.13 1 10.13 4.86 0.1147
AB 1.00 1 1.00 0.4800 0.5382
AC 1.00 1 1.00 0.4800 0.5382
BC 12.25 1 12.25 5.88 0.0938
A2 92.89 1 92.89 44.59 0.0068
B2 6.04 1 6.04 2.90 0.1873
C2 1.75 1 1.75 0.8400 0.4270
Residual 6.25 3 2.08
Cor Total 211.08 12
ANOVA result of the Drug Release(DR) factor Model 276.06 9 30.67 14.72 0.0244 Significant
A-Lipid Conc 98.00 1 98.00 47.04 0.0063
B-Surfactant 10.12 1 10.12 4.86 0.1147
C-Sonication Time 15.13 1 15.13 7.26 0.0741
AB 16.00 1 16.00 7.68 0.0695
AC 25.00 1 25.00 12.00 0.0405
BC 20.25 1 20.25 9.72 0.0526
A2 72.32 1 72.32 34.71 0.0098
B2 0.3214 1 0.3214 0.1543 0.7207
C2 26.04 1 26.04 12.50 0.0385
Residual 6.25 3 2.08
Cor Total 282.31 12
*Sum of Squares, (SS), Mean Square (MSS),

Table 3. Statistical report of Response 1, EE and response 2, DR using BBD.

Response Std. Dev. Mean C.V. % R2 Adjusted R2 Predicted R2 Adeq Precision
1. Entrapment efficiency 1.44 55.62 2.60 0.9704 0.8816 NA⁽1⁾ 10.3679
2. Drug release 1.44 70.23 2.06 0.9779 0.9114 NA⁽1⁾ 13.7252
*⁽1⁾ Case(s) with leverage of 1.0000: Pred R2 and PRESS statistic not defined.
6 S. SHARMA ET AL.

Figure 3. 3-D response surface plots showing the influence of lipid concentration and surfactant conc. (AB), lipid conc and
sonication time (AC), and surfactant conc and sonication time (BC) on the Entrapment efficiency of the SLN.

Figure 4. 2-D contour plots showing the influence of lipid concentration and surfactant conc. (AB), lipid conc and sonication time
(AC), and surfactant conc and sonication time (BC) on the drug release (%)of the SLN.

From the above results, we observed that the con­

centration of surfactant and lipid increase at
a particular level the entrapment efficiency increases
but at the very high concentration entrapment effi­
ciency was goes down. From the above result, we
concluded that the concentration of lipid and sonica­
tion time is increased, entrapment efficiency was
increased at a particular time but at the maximum
time and high concentration of lipid was decrease
the entrapment efficiency.

Design space
Design Space is one of the important aspects of locating
the optimal reasonable region which is based on the
optimisation constraints were used. This model sug­
gested for optimum formulation conditions predicted
was lipid concentration (2.8 mg), surfactant concentra­ Figure 5. Overlay plot.
tion (1.938 mg) and sonication time (5.00 min) gives
the higher response of entrapment efficiency and drug
release. “The expected formulation comebacks were
Particle Size, PDI, and Zeta Potential
identified in the plot (Figure 5) illustrating the values
of EE (62.18%) and drug release (76.99%) which are The effect of lipid and surfactant concentration on the
associated in nearby arrangement with the actual opti­ particle size distribution of TZR loaded SLN prepared
mum formulation conditions (n = 3) EE (61.02%± 1.44) by using GMS and poloxamer. The particle size report
and drug release (75.09%± 1.44”. of TZR loaded SLN is shown in Figure 6.

Figure 6. Report particle size of TZR loaded SLN.
Figure 7. Report of Zeta potential.
Zeta potential: Zeta potential is an important tool
for understanding the state of the nanoparticle surface
and predicting the long-term stability of the nanopar­
ticle. Zeta potential is showed in Figure 7.
Stability studies
The results showed that the entrapment efficiency of
the SLN dispersion stored in the refrigerator was more
compared to the SLN dispersion stored in room
MATERIALS TECHNOLOGY 7
temperature. The evaluation of stability data was
depicted in Table 4.
Scanning Electron microscopy
The results showed that the particles were sphe­
rical with a narrow size distribution, and had
smooth surfaces. No crystals of the drug or aggre­
gation of nanoparticles were found in the sample.
The SEM of an optimized batch was depicted in
Figure 8.
8 S. SHARMA ET AL.

Table 4. Stability study of TZR loaded SLN.

Formulation Immediately (%) 15th day (%) 15th day (%) 30th day (%) 30th (%)
Refrigerator Room temp Refrigerator Room temp
1. 81.22 81.06 78.16 80.00 75.31

Figure 8. SEM of optimised batch.

Figure 9. HPLC analysis.

HPLC analysis
The Final optimised chromatogram was observed as
shown in (Figure 9). The relative retention time was
found to be 3.59 min.
Discussions
Initially, TZR was checked for their solubility profile
and observed that it was practically insoluble in water
and possessing high lipophilicity (Log P). Hence, TZR
solubility was enhanced with incorporation of lipidic
vehicle in the form of SLN. The SLNs are sub-micron
colloidal system with small particle size, largest surface
area, biocompatibility, avoids use of organic solvents
and stable, hence these are preferred in development
of solubility and thereby bioavailability of the drugs.
The first criterion in SLN is the selection of best
suitable solid lipid and accordingly studies were per­
formed and GMS was selected for enhancing the

solubility and bioavailability of TZR. Selection was
based on the ability to develop the SLNs with lowest
particle size, polydispersity index and safety point of
view. Thereafter, appropriate quantity of tween and
span was chosen as surfactants for SLN systems.
Identification of TZR was confirmed with FTIR and
also compatibility studies resulted that there were no
interactions among the TZR with that of solid lipids
and surfactants. Accordingly, formulation batches
were designed and further optimised with the help of
Design Expert software and also with Box Behnken
method.
Critical quality attributes were applied for the
release of the drug and entrapment efficiency. These
are further interpreted statistically as ANOVAF-test.
The optimised batch successfully found to be signifi­
cant with their p value is less than 0.0371 and 0.0244
for entrapment efficiency and drug release, respec­
tively. A surface response curve was plotted with the
variable parameters like concentration of lipids, con­
centration of surfactants and sonication time. At the
optimum level of surfactant and lipid, the entrapment
efficiency was raised and at extreme level goes down.
Moreover, as the concentration of lipid and sonication
time increases the entrapment efficiency was resulted
out better. The desired particle size was achieved using
hot homogenisation method and found to be stable
which was predicted from zeta potential and stability
studies data.
Conclusion
All the preformulation studies of drug and excipients
such as identification, solubility, drug-excipient com­
patibility studies were performed and found to be
satisfactory. Analytical method development with
forced degradation studies was performed and found
to be within criteria. The formulations were developed
and optimised by the Design of Expert (DoE) software.
All the characterisation parameters were found to be
satisfactory. The parameters for the optimised batch
were particle size 470 nm, zeta potential −10.3 mV,
and entrapment efficiency was found to be 59%. The
TZR loaded SLN showed the drug release of 77%.
The hot homogenisation method was beneficial
for the successful incorporation of the poorly
water-soluble drug Tazarotene with high entrap­
ment efficiency. Hence, it was concluding that
solid lipid nanoparticles were used as drug carriers
for lipophilic drugs to facilitate the drug release of
water-insoluble drugs.
Disclosure statement
No potential conflict of interest was reported by the authors.
MATERIALS TECHNOLOGY 9
ORCID
Sanjay Sharma http://orcid.org/0000-0003-3662-4635
Abhishek Kanugo http://orcid.org/0000-0002-5205-5906
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