Deepak sharma final

A Thesis submitted in the partial fulfilment of the requirements for the Degree of
Masters of pharmacy
in
Pharmaceutics
by-
Deepak Chandra Sharma
Enrollment no. 160260801004
Under the supervision of
Dr. G. Gnanarajan
Assistant Professor
And
Mr. Pranshu Tangri
Assistant Professor
Department of Pharmaceutical Sciences
S.G.R.R.I.T.S
1
Division of Pharmaceutical Sciences
Shri Guru Ram Rai Institute of Technology and Sciences
Patel Nager, Dehradun, Uttarakhand
to the
Faculty of Pharmacy
Uttarakhand Technical University, Dehradun
August, 2018

 Introduction
 Disease Profile
 Literature Review
 Aim & Objective
 Need of Study
 Drug Profile
 Pre-formulation Study
 Formulation of Apremilast Emulgel
 Evaluation
 conclusion
 References
 Publications
2

 Emulgels or gellified emulsions are the topical formulations comprising of
emulsion and gel, hence, possessing properties contributed by both. The oil phase,
gelling agent and emulsifying agent constitute the major components of an
emulgel system.
 When gel and emulsion are used in combined form the dosage form are referred
as ‘Emulgel’.
3
EMULSION GEL
EMULGEL

 Hydrophobic drugs can be easily incorporated into gels using
emulsions.
 Avoidance of first pass metabolism.
 Better stability.
 Controlled release.
 Production feasibility & low preparation cost.
 Improve bioavailability.
 Medication can be terminated when needed.
4

 Drug of large particle size not easy to absorb
through the skin.
 Possibility of allergenic reactions.
 Occurrence of bubble during formulation of
emulgel.
5

 Psoriasis is defined as a persistent skin disease causes cell to build rapidly on the
surface of the skin, forming thick silvery scales, itchy, dry and red patche.
 These patches are referred as plaque which usually occur on the elbow, knees,
legs, scalp, lower back, face, palm and sole of the feet, nails.
 Symptoms
 Patches of skin
 Dry, swollen and inflamed
 Pain, itching and burning
6
Fig.1 Schematic Comparison between Healthy Skin
And Psoriasis Affected Skin

7
Fig.2 Schematic Treatment For Psoriasis: Different Types Of Treatment Used
Depending Upon Severity.

 Dinesh Chandra*, et al.,(2013) developed and evaluate Etroxicob gel by using different gelling agents
and permeation enhancer. Toxicol is NSAID category drug, which is selectively COX 2 inhibitor. oral
administration of Etroxicob cause GIT irritation and hepatotoxicity that’s why we use gel-like topical
approach. Carbapol, Na CMC and HPMC using as a gelling agent and propyl glycol, oleic acid and mentha
oil taking as a permeability enhancer. All the emulgel formulation were evaluated for pH, spreadability,
drug release, viscosity, physical appearance and ex-vivo, and skin irritation test. A,B,C three batch of the
formulation were prepared by the different gelling agent and permeation enhancer. During the evaluation
batch, A selected for further anti-inflammatory activity. Batch A prepared by Carbapol with propyl glycol
(10%) and oleic acid (2%) were applicable for topical use and it shows better drug release and anti-
inflammatory effect as compare to a marketed product.
 Gupta Saurabh* et al.,(2015) worked on formulation and characterization of clindamycin phosphate
emulgel. aim was present study to development of clindamycin phosphate emulgel using Carbapol 934 and
HPMC 2930 as a gelling agent. Gelling agent use for forming gel base for emulgel formulation. Formula
was optimized with the help of factorial design. All the developed emulgel formulation were evaluated for
spreadability, pH, viscosity, extrudability, Drug content, physical appearance and in-vitro release profile. 8

AIM:- Formulation and Evaluation of Apremilast Emulgel for topical drug
delivery
OBJECTIVE:-
 To perform the compatibility studies of the drug and polymer by FTIR.
 To prepare calibration curve of Apremilast.
 To perform pre-formulation studies of the drug.
 To formulate the drug-loaded Emulgel for the delivery of hydrophobic drug
topically in different polymer.
 Evaluation of prepared Emulgel.
 Plot and establish various release kinetic model.
 To conduct stability study of Emulgel.
9

To develop topical formulation incorporating hydrophobic drug which is
not possible by other semisolid formulation, only possible by
formulating Emulgel(Emulsion + Gel).
Because, many widely used topical agents like ointments, creams,
lotions have many disadvantages. They are sticky in nature causing
uneasiness to the patient when applied, have lesser spreading coefficient
so applied by rubbing and they also exhibit the problem of stability
Treatment for skin infection like psoriasis, fungal infection by avoiding
first pass metabolism hence increasing bioavailability of the drug.
10

APREMILAST
 Category: Anti-Psoriasis Agents, Anti-inflammatory Agents,
Dermatologic Agents
 Molecular mass:- 460.501 g/mol
 Chemical Formula:- C22H24N2O7S
 Melting point:- 150-152 ºc
 Solubility:- very slightly soluble in distilled water, pH 7.2,
freely soluble in ethanol , methanol and organic solvent.
11

Pharmacokinetic Properties
Absorption GIT
Bioavailability (%) 60 - 70%
Distribution 73%,
Metabolism Metabolize through Liver
Excretion
58% Through Urine
39% Through Faeces
Half Life 6-8 Hour
12
Pharmacokinetics
Table 1: Pharmacokinetic properties of Apremilast

1. Preformulation study related to drug
1.1. Melting point
.
13
Sr. No Method Experimental
value
Reported value
1 Capillary method 150-153 ºC 150-152ºC
Melting point range was found to be 150-153ºC which is similar to that of the
reported value.
Table 2: Results of melting point study

1.2 Solubility Study
14
Sr. No. Solvent Solubility Solubility
(mg/ml)
Solubility range
IP(mg/ml)
1 Water Very slightly
soluble
0.2 0.1-1
2 Methanol Freely
soluble
175 100-1000
3 Ethanol Freely
soluble
163 100-1000
4 Phosphate buffer pH
7.2 : Methanol[9:1]
Very slightly
soluble
0.7 0.1-1
1.3 Partition coefficient
The partition coefficient of apremilast was found to be 3.14 indicating the high
lipophilicity of the drug.
Table 3: Results of solubility study in different solvent

1.4 Calibration curve
15
y = 0.0052x + 0.0097
R² = 0.9967
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0 10 20 30 40 50 60 70
Fig.3 Calibration curve of Apremilast in Phosphate buffer 7.4:
Methanol (9:1)
Abs
Linear (Abs)
Sr. No. Concentration(µg/ml) Absorbance
1 10 0.0584
2 20 0.1175
3 30 0.1687
4 40 0.2150
5 50 0.2804
6 60 0.3179
Table 4: Calibration Curve of Apremilast in Phosphate buffer 7.4: Methanol (9:1)

Sr. No Concentration (µg/ml) Absorbance
1 10 0.1740
2 20 0.3898
3 30 0.7004
4 40 0.7828
5 50 1.0131
6 70 1.2139
16
y = 0.0207x - 0.0295
R² = 0.9994
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 10 20 30 40 50 60 70
Calibration Curve of Apremilast In Methanol
Fig.4 Calibration curve of Apremilast in methanol
Table 5: Calibration Curve of Apremilast in Methanol

1.5 Drug and polymer interaction
17
Fig. 5 FTIR of Apremilast sample
Sr. No. Observed wavenumber(cm-1) Standard range (cm-1) Interpretation
1 1309 1350-1000 C-N, Amines
2 1374 1375-1300 S=O, Sulfoxides
3 3081 3150-3050 C-H, Aromatic (STRETCH)
4 3362 3500-3100 N-H, AMIDE
5 1705 1725-1705 C=O, KETONE
6 1597.7 1700-1475 C=C, Aromatic
7 873 900-790 C-H, Aromatic(Bend)
Table 6: FTIR Interpretation of Apremilast

 Drug+carbapol 934
18
Discussion: FTIR was performed to observed drug-excipient
compatibility. Apremilast and Carbopol 934 IR spectra reveal that there
were no significant changes in the absorption peaks of the drug-polymer
mixtures and therefore it can be concluded that there was no interaction of
polymer with the drug and was compatible with each other.
Fig. 6 FTIR of drug + carbapol 934
Carbapol 934+Drug Carbapol 934

 Xanthan gum+Drug
19
Discussion: FTIR was performed to observed drug-excipient compatibility.
Apremilast and Xanthun gum IR spectra reveal that there were no
significant changes in the absorption peaks of the drug-polymer mixtures
and therefore it can be concluded that there was no interaction of polymer
with the drug and was compatible with each other.
Xanthan gum+Drug Xanthan gum
Fig. 7 FTIR of drug + Xanthum Gum

20
Discussion: FTIR was performed to observed drug-excipient
compatibility. Apremilast and Sodium CMC IR spectra reveal that there
were no significant changes in the absorption peaks of the drug-polymer
mixtures and therefore it can be concluded that there was no interaction of
polymer with the drug and was compatible with each other.
Sodium CMC+Drug Sodium CMC
Fig. 8 FTIR of drug + Sodium CMC

21
 HPMC K4M+Drug
Discussion: FTIR was performed to observed drug-excipient compatibility.
Apremilast and HPMC K4M IR spectra reveal that there were no significant
changes in the absorption peaks of the drug-polymer mixtures and therefore it
can be concluded that there was no interaction of polymer with the drug and
was compatible with each other
HPMC K4M+Drug HPMC K4M
Fig. 9 FTIR of drug + HPMC K4M

Ingredient(%w/w) F1 F2 F3 F4 F5 F6 F7 F8
Apremilast 1 1 1 1 1 1 1 1
Carbapol 934 0.5 1 - - - - - -
HPMC K4M - - 0.5 1 - - - -
Xanthan gum - - - - 0.5 1 - -
Na CMC - - - - - - 0.5 1
Span 80 1 1 1 1 1 1 1 1
Tween 80 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Liquid paraffin 13 13 13 13 13 13 13 13
Mentha oil 8 8 8 8 8 8 8 8
Propyl paraben 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
TEA 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7
Glutaraldehyde 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3
Iso-propyl myristerate 5 5 5 5 5 5 5 5
Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
22
Table 7: Composition for preparing Apremilast emulgel of different batches

23
EMULSION GEL
EMULGEL
INCORPERATION INTO GEL
BASE
EMULGEL
Emulsification
STIRRING

1. Physical appearance
25
Sr.No. Formulation code Colour Phase
separation
Grittiness
1. F1 White NA NA
2. F2 White NA NA
3. F3 White NA NA
4. F4 White NA NA
5. F5 White NA NA
6. F7 White NA NA
7. F7 White NA NA
8. F8 White NA NA
The physical appearance was examined visually, Parameters like color, separation of
phases and grittiness were conducted and recorded. All the parameters show stable
physical appearance.
Table 8: Physical Characteristics

2. Measurement of pH
26
Formulation
code
F1 F2 F3 F4 F5 F6 F7 F8
pH 5.24 5.73 4.92 5.03 5.71 5.20 4.34 4.78
The pH of the Emulgel formulations was in range 5.5 to 5.73 which lies in
the normal pH range of the skin and would not produce any skin irritation
Table 9: pH of Emulgel Formulation

3. Spreadability
It indicates how easily the Emulgel will be spread on the affected area by
small amount of shear.
27
Formulation F1 F2 F3 F4 F5 F6 F7 F8
Spreadability
(cm2)
27.98 23.08 17.80 15.91 21.73 20.92 18.10 17.75
4. Extrudability
From the study it absolutely was found that formulation F7 and F8 with polymer Na CMC need
high shear, whereas F1 and F2 with carbapol show less extrudability.
Extrudability
(g/cm2)
17.54 15.87 19.77 18.98 17.28 18.11 20.73 21.59
Table 10: Spreadability of Emulgel Formulations
Table 11: Extrudability Of Emulgel Formulations

5. Viscosity
The viscosity of all formulation was conducted at totally different rate and it was
found that formulation F1 shows high consistence at each 50 and 100 RPM. The
results are recorded in table
28
RPM Viscosity(cp)
F1 F2 F3 F4 F5 F6 F7 F8
50 7314 7145 7247 7174 7114 7201 7184 7207
100 5348 5093 5021 5207 5343 5277 5273 5173
Table 12: Viscosity of Emulgel Formulations

6.Centrifuge test
In order to assess the stability of the prepared emulgel, centrifuge test was
performed to observed any separation of layers and from this study it had been
found that each one prepared formulation were stable as there was no separation
of phases were ascertained.
7.Drug content
To see the impact of polymer on concentration of the drug, drug content was
performed on all ready formulation and it had been found that each one
formulation area unit inside the limit i.e. from 95-102%
29
99.87 99.71
97.51
95.12
101.27 100.98
98.43
96.49
92
94
96
98
100
102
F1 F2 F3 F4 F5 F6 F7 F8
Series1
fig. 9 Graphical representation of Drug content of Emulgel

30
Franz diffusion cell
Was used
Semi permeable egg
membrane used
Phosphate buffer pH 5.5 +
methanol [9:1]
1ml sample was withdrawn and
subsequently filled with disso
medium
Temperature of the cell was
maintained at 37 ± 2°C.
Medium stirred
at 50rpm
Analyzed with uv spectrophotometry
and cumulative release was calculated
8. In-Vitro drug release study

From in-vitro diffusion study it was found that the Carbapol emulgel with low
concentration of polymer F1 shows maximum release. The release pattern with Carbapol
emulgel was better than other polymer formulation. Formulation F1 from Carbapol polymer
and formulation F5 from xanthan gum polymer shows best result.
0
10
20
30
40
50
60
70
0 200 400 600
%CDR
TIME ( IN MIN)
IN VITRO DIFFUSION STUDY
F1
F2
F3
F4
F5
F6
F7
F8
31
Fig. 10 in-vitro diffusion study of prepared formulation F1-F8

The results of In vitro release from formulations were plotted in different kinetic
models like Zero order, First order, Higuchi plot and KorsmeyerPeppas plot and
are represented in Figure. The regression coefficient value R2 is reported for all
formulation. The release data of best formulation F1 and F5 follows Higuchi
model.
32
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
0.00 100.00 200.00 300.00 400.00 500.00 600.00
%CUMMULATIVERELEASE
TIME (IN MINUTE)
ZERO ORDER
F1
F2
F3
F4
F5
F6
F7
F8
FIG. 11 Zero order release plot of Emulgel formulations

0
1
2
3
4
5
6
7
0 1 2 3 4 5 6 7 8 9
%logCR
TIME (IN HOUR)
FIRST ORDER F1
F2
F3
F4
F5
F6
F7
F8
33
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
0 5 10 15 20 25
%CUMMULATIVECR
SQUARE ROOT OF TIME
HIGUCHI MODEL
F1
F2
F3
F4
F6
F7
F8
FIG. 12First order release plot of Emulgel formulations
FIG. 13 Higuchi release plot of Emulgel formulations

34
0
1
2
3
4
5
6
7
0 0.5 1 1.5 2 2.5 3
%LOGCUMMULATIVE
RELEASE
LOG TIME IN HOURS
KORSMEYER PEPPAS MODEL
F1
F2
F3
F4
F5
F6
F7
F8

Formulation Zero order First order Higuchi plot KorsmeyerPeppas plot Possible
mechanism of
drug release
R2 R2 R2 R2 n
F1 0.974 0.9889 0.9971 0.9802 0.842 Higuchi model,
Non-Fickian
F2 0.911 0.9529 0.9897 0.8191 0.9819 Higuchi model ,
Non-Fickian
F3 0.992 0.9947 0.9239 0.6541 0.8904 First order, Non-
Fickian
F4 0.980 0.9929 0.9181 0.7546 0.8564 First order, Non-
Fickian
F5 0.955 0.9789 0.9892 0.6584 0.9651 Higuchi model,
Non-Fickian
F6 0.975 0.9972 0.9193 0.7841 0.9380 First order, Non-
Fickian
F7 0.964 0.9824 0.9187 0.9968 0.8087 KorsmeyerPeppas
model, Non-
Fickian
F8 0.944 0.9941 0.9287 0.7844 0.8514 First order, Non-
Fickian
35
Table. 12 Release Kinetic of Emulgel Formulations

10. STABILITY TEST:
Every sample was subjected to physical appearance, phase separation and drug
content. All prepared formulations were found to be physically stable and no
effect was seen on drug content.
36
Sr. No. Formulation
code
Colour Grittiness
1. F1 White None
2. F2 White None
3. F3 White None
4. F4 White None
5. F5 White None
6. F7 White None
7. F7 White None
8. F8 White None
Table. 13 Physical characteristics

Drug content
(%)
98.92 97.71 95.51 95.12 99.87 99.18 97.43 95.49
37
Phase separation NA NA NA NA NA NA NA NA
 DRUG CONTENT
 PHASE SEPARATION
Table 14:Drug content of prepared emulgel
Table 15: Phase separation of prepared emulgel

 The present study was conducted to prepare topical delivery of Apremilast in the form of Emulgel.
Various pre-formulation studies such as FTIR, melting point, solubility and partition coefficient
were performed for the selection of polymers and solvents.
 Evaluation parameters such as appearance, pH, Viscosity, Spreadability, Extrudability, Drug
Content, centrifuge test and In-Vitro Drug Release profile were conducted and it was concluded that
all prepared formulation was stable for the application of local sites such as skin. From the
cumulative % release it was found that formulation F1 with carbapol having low concentration
shows maximum release in 8hr (57.49%) and from this study it can be concluded that delivery of
drug across the skin is mainly depend upon concentration of polymer as less is the concentration
more will be the absorption of drug through skin.
 Thus from all evaluation parameters it can be concluded that Apremilast Emulgel with carbapol as a
polymer is a optimized formulation. From release kinetic it was found that the best fit model was
Higuchi model following Non-Fickian diffusion. In stability study, all the formulations were found
to be physically stable and no effect was observed in the drug content of all formulation.
38

1. Burns T, Breathnach S, Cox N and Griffiths. Rook’s Textbook of Dermatology Volume 1, Eighth
Edition. Blackwell Publishing; 2010.
2. Ansel, H.C., Allen Jr, L.V., Popovich, N.G. Pharmaceutical Dosage Forms and Drug Delivery
Systems, 7th edition. Lippincott Williams and Wilkins, New York; 1999.
3. Sarah Dubois Declercqet all. Promising new treatments for psoriasis. Hindawi in an emergent novel
drug delivery technology: Emulgel. Journal of controlled release 2013;171: 122-32.
4. Baibhav J, Singh Gurpreet S, Rana AC, Seema S and Singla V. Emulgel: A comprehensive review
on recent advancement on topical drug delivery. International Research journal of pharmacy 2011;
2: 77-70.
5. Shailendra Kumar Sah, Ashutosh Badola, Bipin Kumar Nayak. Emulgel: magnifing the application
of topical drug delivery. Indian Journal of Pharmaceutical & Biological Research 2017; 5(1):25-33.
6. Rathbone MJ, Hadgraft J, Roberts MS, Lane ME. Modified –release drug delivery technology 2nd ed.
Informa healthcare; 2: 273-271.
39

 Review article on “APPLICATIONS AND APPROACHES FOR EMULGELS”
published in WORLD JOURNAL OF PHARMACEUTICAL RESEARCH(WJPR).
 Research article on “METHOD DEVELOPMENT OF APREMILAST(API) IN
METHANOL BY UV-VISIBLE SPECTROPHOTOMETRY” published at
International Journal of Trend in Scientific Research and Development (IJTSRD).
 Research article on “DESIGN AND CHARACTERIZATION OF APREMILAST
LOADED EMULGEL FOR TOPICAL TREATMENT” has been ACCEPTED with
content unaltered to publish with International Journal of Pharmacy and Biological
Sciences (IJPBS) (Int. J. Pharm. Biol. Sci.) Electronic-ISSN:2230-7605 and print-
ISSN: 2321-3272, Volume 8; Issue 3; 2018.
 Poster presentation at “69thIndian Pharmaceutical Congress(IPC) held on 22nd to 24th
2017 ”. 40

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