Vol 3, Issue 3, 2021 (128-138)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : y.w.wardhana@unpad.ac.id (Y. W. Wardhana)
https://doi.org/10.24198/idjp.v3i3.36140
2021 Y. W. Wardhana et al
Ophthalmic Release of in situ gel Ciprofloxacin Hci Based on Combination of
Hypromellose and Hci
Yoga Windhu Wardhana1,2*, Wieke Budiati2, Rizky Dwi Oktavia2, Kalista Tritama
Widyanti2, Insan Sunan Kurniawansyah1,2, Yedi Herdiana1
1 Department of Pharmaceutic and Pharmaceuticals Technology, Faculty of Pharmacy,
Universitas Padjadjaran (UNPAD), Indonesia
2 Central Study of Pharmaceuticals Development, Faculty of Pharmacy, Universitas
Padjadjaran (UNPAD), Indonesia
3 Faculty of Pharmacy, Universitas Padjadjaran (UNPAD), Indonesia
e-mail : y.w.wardhana@unpad.ac.id
Submitted :16/10/2021, Revised :04/11/2021, Accepted 05/11/2021, Published :07/02/2022
Abstract
The development for ophthalmic delivery was purposed to achieve optimum drug
loading for ocular therapeutic benefits. An adequate dose of the drug is needed to
absorb in the conjunctival sac to take effect. In situ gel preparation was expected to
provide these needs with the polymer aid that makes the droplets suddenly
coagulate in the eye area to maintain the drug dose. The in situ gel dosage form is
desired to overcome the poor bioavailability of conventional ciprofloxacin HCl eye
drops on the market. Thus, this work was studied using two cellulose polymers such
as hydroxyl propyl cellulose (HPC) and hydroxypropyl methylcellulose (HMPC)
as a gelling forming agent. The effect of the in situ ophthalmic quality of the gel
due to the two individual polymers separately and their combined use was
investigated. The in situ gel quality includes the ability of gel-forming under the
influence of varying temperature and stirring frequency difference (as a rheological
study) was tested together with the drug release model model. Other ophthalmic
preparation quality parameters such as clarity, pH measurement, drug content
determination, sterility, and antibacterial activity have been evaluated. However,
overall in situ gel formulation developed was of better quality compared to the
conventional one. Consideration of the choice of cellulose derivative polymer type
is seen to affect the quality of controlled release kinetics models.
Keywords: Ophthalmic gel, Ciprofloxacin HCl, HPMC, HPC, Drug release
kinetics
1. Introduction
Ophthalmic delivery systems were
considered the attainment and retention of
optimum therapeutic levels for the
treatment of ocular diseases. Various
conventional ophthalmic formulations on
the market such as eye drops, suspensions,
and ointments have very poor restrain
drugs due to their rapid washout during
lachrymation in the eyes. Usually applied
Y. W. Wardhana et al / Indo J Pharm 3 (2021) 128-138
129
as solutions or suspensions which
elimination rapidly observed with ends in
poor drug bioavailability. In the case of
highly viscous dosage form, such as
ointments give blurred vision and patient
compliance (Al-Kassas et al., 2009; Dash
et al., 2010; Jain et al., 2008; Makwana et
al., 2015).
So, an ideal dosage form with
convenience and safety for ocular therapy
is needed. Especially for an eye infection
treatment which needs to care
immediately and the precorneal residence
time of drugs. For this purpose, designing
ophthalmic preparation containing
antibiotic should optimize the absorption
of the drug and minimize drug loss before
penetration the cornea (Rathor, 2010).
Recently, various approaches have been
reported to delay drug elimination from
the conjunctival sac (Kurniawansyah et
al., 2018). One of these reports using the
hydrogel system based on the concept of
in situ gel formation. The system with
polymers contains shown ability of sol–
to–gel phase transitions due to a specific
physicochemical parameter alteration
(ionic strengths, pH, or temperature) in the
circumstances (Kurniawansyah et al.,
2018). The gelation was affected by pH
shifting such as cellulose phthalate
derivative (Makwana et al., 2015), or by
existence cations such as deacetylated
gellan gum (Zhu L et al., 2015) and
alginate derivate (Al-Kassas et al., 2009;
Sharma et al., 2014; Makwana et al.,
2015), or by temperature alteration such as
poloxamer (Varshosaz et al., 2008; Jain et
al., 2008) and (hydroxyl propyl or ethyl or
methyl) cellulose derivative (Vigani et al.,
2019; Al-Kassas RS et al., 2009; Dash et
al., 2010; Jain et al., 2008; Makwana et al.,
2015). From all those gelation factors,
only thermosensitive which has suitable
for the nasolacrimal condition. Therefore,
in gel form, the polymers were lowering
the drying nasolacrimal and have
mucoadhesive properties (Kurniawansyah
et al., 2019). Besides those, the
application within situ gel was user-
friendly, practically easy to prepare,
improving therapy efficiency and patient
comfort.
In this present work, the preparation
and evaluation of in situ gel Ciprofloxacin
hydrochloride (CFH) dosage form were
conducted. This antibiotic under
fluoroquinolone groups commonly used
because it has a broad-spectrum
antimicrobial activity(Makwana et al.,
2015). Effectively proven for ocular
infection, such as conjunctivitis and
keratoconjunctivitis (Dash et al., 2010). It
is highly active for Gram-negative aerobic
bacteria including Enterobacteriaceae,
Pseudomonas aeruginosa, Haemophilus,
and Neisseriaei also effective against
many Gram-positive aerobic pathogens
including penicillinase-producing and
methicillin-resistant Staphylococci
(Makwana et al., 2015). The activity
related with inhibiting the DNA girase
(topoisomerase II) and topoisomerase IV
synthesis of the microorganism
(Varshosaz et al., 2008). The efficacy of
the marketed conventional eye drop in
0.3% solution was restricted by poor
bioavailability (Al-Kassas et al., 2009).
Then to overcome the problem of the
ophthalmic bioavailability of CFH, a
polymer with low sensitivity to
temperature alternation may select. So, the
study of the combination of Hydroxy
Propyl Cellulose (HPC) and Hydroxy
Propyl Methyl Cellulose (HPMC) as
known weak gelling agents at lower
Y. W. Wardhana et al / Indo J Pharm 3 (2021) 128-138
130
temperatures from each one as in-situ gel
ability in eye gel dosage form conducted.
Figure 1. Structure of ciprofloxacin
hydrochloride (Sharma et al. 2010)
MATERIALS AND METHODS
2. Materials
Ciprofloxacin Hydrochloride (CFH)
was purchased from Zhejiang Langhua
Pharmaceutical Co. Ltd. (China),
Hydroxypropyl Cellulose (grade HPC–H)
was purchased from Nippon Soda Co.,
Ltd. (Japan), and Hydroxypropyl methyl
Cellulose (grade Metolose 90SH–4000)
was obtained from Shin–Etsu Chemical
Co. Ltd. (Japan). The bacterials tested
were Bacillus subtilis ATCC 6633,
Pseudomonas aeruginosa ATCC 9027,
Staphylococcus aureus ATCC 25923 and
the fungus was Candida albicans ATCC
25923. All other chemicals and solvents
used were commercially available
products of analytical grade.
3. Methods
Compatibility studies
The CFH and the polymers used
(HPC and HPMC) as following both
compatibilities were checked by FTIR (IR
Prestige-21 Shimadzu, Japan). Drug
content was detected by UV–Vis
Spectrophotometer (SPECORD 200,
Analytic Jena, Germany) at a wavelength
of 270 nm.
3.1 In Situ Gel Formulations
The developed in situ gel
formulations were prepared with various
polymers (HPC and HPMC)
concentrations as follows in table 1. The
ophthalmic in situ gel was prepared as
follows. In a different container, HPC and
HPMC were dispersed in demineralized
water and stirred slowly with a magnetic
stirrer. Care was taken to avoid lumps of
those polymers during stirring. Then let it
sit overnight to swelling in transparency
colloids. In another container mix CFH,
Benzalkonium Chloride, and NaCl in
demineralized water stir until
homogenous. Then mix the CFH solution
with a polymer solution (HPC or HPMC
or a mixture of both) and add PEG 400
stirred until homogeneous. Before adding
the remaining demineralized water check
the pH of the solution, adjust to pH 4.5
with 0.1 N hydrochloric acids in small
increments. If the pH is reached, stir
homogeneously.
Table 1. Formulation of ophthalmic in situ gel preparations
Ingredients
Concentrations (% b/v)
A1
B1
C1
A2
B2
C2
A3
B3
C3
CFH
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
HPC
0.2
–
0.3
0.3
–
0.2
0.4
–
0.1
HPMC
–
0.2
0.1
–
0.3
0.2
–
0.4
0.3
Benzalkonium Chloride
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
Polyethylen Glycol 400
(PEG 400)
1
1
1
1
1
1
1
1
1
Y. W. Wardhana et al / Indo J Pharm 3 (2021) 128-138
131
NaCl
0.77
0.77
0.86
0.77
0.77
0.86
0.77
0.77
0.86
Aquabidest add …. mL
100
100
100
100
100
100
100
100
100
Description : A : Hydrogel formulation with HPC C : Hydrogel formulation with
B : Hydrogel Formulation with HPMC mixed both HPC and HPMC
3.2 Evaluation of the Formulation
Visual appearances
Checked by observing changes in color,
odor, and clarity visually on the day of
production and after 28th days of storage.
3.3 pH and Viscosity measurement
The pH measurement of each formulation
without any dilution using a pH meter
(Hanna®, Japan) was calibrated before use
with a buffered solution at pH 4 and 7.
Meanwhile, the viscosity measurements
were carried out using Brookfield
viscometer model DVII. The developed
formulations were placed in the sampler
tube using spindle no. 2. To proven the
gelling effect by temperature,
measurements are carried out at two
temperatures namely at room temperature
(25oC) and body temperature (37oC). For
rheological studies, the measurements are
measured repeatedly at different speeds on
6, 12, 30, and 60 rpm.
3.4 Analysis of ciprofloxacin
The drug content of ciprofloxacin
formulations was determined by
dissolving an accurately weighed quantity
of 0.1 ml formulation and diluted to 100
ml with phosphate buffer pH 7.4. The
solutions were then filtered through a 0.45
m membrane filter and analyzed for
ciprofloxacin content by UV–Vis
spectrophotometer at 270 nm.
3.5 Sterility Test
The product was sterilized by autoclave at
121oC for 15 minutes. Conducted with
Fluid Thioglycollate (FTM) and Tryptone
Soya Broth (TSB) media. Different media
are inoculated with different types of
microorganisms. The FTM was planted
by Bacillus subtilis ATCC 6633 and TSB
was planted by Candida albicans
ATCC 25923. Aseptically inoculated
directly to each test preparation into a test
tube FTM and TSB media and then
incubated at 30–35oC and 20–25oC,
respectively for not less than 14 days. The
occurrence of turbidity in the test tube was
observed every day.
3.6 Antibacterial Activity
Sample solution (as in situ gel preparations)
and standard solutions (as CFH solution)
were aseptically filled into each reservoir
Petri dishes about 20 µl using a
micropipette. In separate Petri dishes were
containing bacterial tested Staphylococcus
aureus ATCC 25923 and Pseudomonas
aeruginosa ATCC 9027, that has been
diluted in Mueller Hinton agar (MHA).
Then incubated at 37oC for 18–24 hours.
Measured and recorded diameter clear zone
(zone-lysis). Calculate the potential of CFH
in all formulation dosage forms.
3.7 In Vitro release studies
In vitro release diffusion tested using
phosphate buffer pH 7.4 as STF (Simulated
Tear Fluid) for dissolution medium, which
is equivalent to the pH of the lachrymal
fluid. The in vitro release study was
performed by Franz diffusion apparatus
132
with the speed of rotation maintained at 100
rpm. The apparatus was placed in a water
bath to maintained medium temperature
(maintained at 37 ± 0.5°C). The samples
which were collected from the in vitro
diffusion test at various time intervals and
analyzed the drug concentration using a
UV-Visible Spectrophotometry at 270 nm.
4. RESULTS AND DISCUSSION
The quality of the in situ gel preparation
that has been made needs to be observed for
evaluation.
4.1 Compatibility studies
The choice of ingredients in the formulation
needs to be studied before there is a risk that
reduces stability. For this purpose, the FTIR
examination of the ingredients to be mixed
is examined as shown in Fig. 2.
The FTIR technique was used as a
compatibility study between CFH and two
polymers utilized. The spectral study of the
spectrograph (Fig. 2) and spectrums (Table
2) shown that no interaction indicated by no
change in the spectrograph patterns in the
drug-polymer mixture. That means the
polymer is safe for formulation because it
does not change the functional groups of
the active pharmaceutical ingredients.
4.2 Evaluation of the formulation
All the formulations prepared quality were
evaluated for clarity, pH measurement,
viscosity, and drug contents.
4.3 Visual Appearance
The clarity of visual appearance was
conducted by observing the solution against
white and black background under
fluorescent light. The solution was found to
be clear and free from particulate matter.
Preparation inspections made from the
beginning up to 28 days of storage remain
unchanged significantly as shown in Table
3. This shows that the preparation made is
quite stable within 28 days of storage.
4.4 pH Measurement and Viscosity
The pH of preparations was adjusted for
around 4.5 according to USP monograph
(3.5–5.5) and to avoid CFH degradations.
From rheological studies found a decrease
in viscosity due to increased speed. The
viscosity behavior was described as a
pseudoplastic type as illustrated in Fig. 3
and Table 4. The concentration increased of
HPC and HPMC did not affect the
rheogram profile. Likewise, the
combination of both does not give a
difference in the rheogram profile.
The viscosity changes may influenced by
temperature and pH, the test at the same
speed showed that an increase in
temperature and pH actually decreases the
viscosity of the preparations as shown in
Table 5.
133
Original Material
Mixture of Material for preparations
Figure 2. The infrared spectrums of (A) CFH, (B) HPC, (C) HPMC, the combination of both ((D)
CFH–HPC and (E) CFH–HPMC) and (F) all of combinations (CFH–HPC–HPMC).
4.5 Sterility Tested
The requirement of ocular dosage form has
to be sterile after the final sterilization by
autoclave at 121oC for 15 minutes. The
sterility tested results that all formulation in
sterile after final sterilization as shown in
Table 6.
Table 2. The functional groups of FTIR spectrums from CFH and polymers
Functional Groups
Spectrum IR (cm-1)
CFH
CFH with
HPC + HPMC
O- H
3700- 3500
3529.88
3550.86
N- H
3400- 3300
3378.47
3356.78
C- H aromatic
3020-3000
3100.70
3177.86
5007501000125015001750200025003000350040004500
1/cm
15
22,5
30
37,5
45
52,5
60
67,5
75
82,5
90
97,5
%T
3529,88
3378,47
3100,70
3012,94
2690,81
2464,17
1709,00
1625,10
1448,60
1273,07
27-01-2014 ATV STD
5007501000125015001750200025003000350040004500
1/cm
0
5
10
15
20
25
30
35
40
45
50
55
%T
3680,34
3530,85
3177,86
2701,42
1792,91
1707,08
1552,76
20 02 14 hpmc+cipro
5007501000125015001750200025003000350040004500
1/cm
10
15
20
25
30
35
40
45
50
55
60
65
%T
3500,95
2936,75
2079,35
1651,14
1060,89
20 02 14 hpmc-1
5007501000125015001750200025003000350040004500
1/cm
0
5
10
15
20
25
30
35
40
45
50
55
%T
3680,34
3530,85
3177,86
2701,42
1792,91
1707,08
1552,76
20 02 14 hpmc+cipro
C
A
B
D
E
F
134
O- H carboxylic acid
3400-2400
2690.81
2701.40
C = O
1760- 1690
1739.00
1739.28
C = C
1600- 1470
1638.20
1662.76
C- N
1360- 1250
1273.07
1273.10
1. Table 3. Physicochemical Evaluation of Formulations
2.
Visual appearance
pH
Viscosity (cPs)
Drug Contents (%w/v)
Formu-
lations
A
B
C
A
B
C
A
B
C
A
B
C
1
Dilute, Clearly,
Transparent, Odorless
4.60
4.60
4.55
16
21
29.5
102.70+
0.06
99.24+
0.08
100.87+
0.13
2
Dilute, Clearly,
Transparent, Odorless
4.50
4.50
4.60
20.7
22.8
28
100.73+
0.17
101.61+
0.13
101.40+
0.14
3
Dilute, Clearly,
Transparent, Odorless
4.50
4.50
4.58
24
25
30.7
101.36+
0.12
102.47+
0.11
102.65+
0.09
Description : A : Hydrogel formulation with HPC C : Hydrogel formulation with
B : Hydrogel Formulation with HPMC mixed both HPC and HPMC
Table 4. Rheology profile of formulations in various spindle speed
Formu-
lations
Viscosity (cPs)
20 rpm
30 rpm
50 rpm
60 rpm
100 rpm
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
1
31.8
33
41
24.5
25
31.5
16
20
25.6
13.9
18
21.8
5.3
19
15.5
2
40.4
58
42.8
31.5
40
33.6
20.7
32
26.8
17.8
24
22.8
7.9
19
16.6
3
46.3
63
45.3
35.9
43
36.2
24
37
28.4
21.3
33
24
9.6
26
18.2
Description : A : Hydrogel formulation with HPC C : Hydrogel formulation with
B : Hydrogel Formulation with HPMC mixed both HPC and HPMC
Figure 3. The rheogram profile of formulation :
a) 1 (with HPC 0.2%, HMPC 0.2% and HPC : HMPC = 0.3% : 0.1%)
b) 2 (with HPC 0.3%, HMPC 0.3% and HPC : HMPC = 0.2% : 0.2%)
c) 3 (with HPC 0.4%, HMPC 0.4% and HPC : HMPC = 0.1% : 0.3%)
135
Figure 4. The in vitro release profile of formulation :
a) 1 (with HPC 0.2%, HMPC 0.2% and HPC : HMPC = 0.3% : 0.1%)
b) 2 (with HPC 0.3%, HMPC 0.3% and HPC : HMPC = 0.2% : 0.2%)
c) 3 (with HPC 0.4%, HMPC 0.4% and HPC : HMPC = 0.1% : 0.3%)
4.6 Antimicrobial activity assays
The potency of antimicrobial activity of
formulations were carried out against gram
positive (Staphylococcus aureus ATCC
25923) and gram-negative (Pseudomonas
aeruginosa ATCC 9027) organisms. It
appears that the antimicrobial potency is
not greatly influenced by the viscosity or
drug release model from the formulation.
The comparison of inhibition zones was
evaluated to have better activity against
gram-negative as shown Table 7.
Table 5. Viscosity measurement in different temperature and pH
Description : A : Hydrogel formulation with HPC C : Hydrogel formulation with
B : Hydrogel Formulation with HPMC mixed both HPC and HPMC
Formu-
lations
At 25oC
At 37oC (with STF)
Viskosity (cPs)
50 rpm
pH
Viskosity (cPs)
50 rpm
pH
A
B
C
A
B
C
A
B
C
A
B
C
1
16
5.1
28.7
4.5
4.82
4.55
13
4.5
25
6.5
5.48
6.5
2
21
8.6
27.5
4.5
4.90
4.6
15
7.2
23.6
6.7
5.59
6.65
3
25
14.1
29.2
4.5
4.67
4.5
20
12.7
26.2
6.7
5.18
6.7
136
Table 6. The sterility tested on CFH formulations
Day
Formulations
A1–3
B1–3
C1–3
FTM
TSB
FTM
TSB
FTM
TSB
1
-
-
-
-
-
-
2
-
-
-
-
-
-
3
-
-
-
-
-
-
4
-
-
-
-
-
-
5
-
-
-
-
-
-
6
-
-
-
-
-
-
7
-
-
-
-
-
-
Day
Formulations
A1–3
B1–3
C1–3
FTM
TSB
FTM
TSB
FTM
TSB
8
-
-
-
-
-
-
9
-
-
-
-
-
-
10
-
-
-
-
-
-
11
-
-
-
-
-
-
12
-
-
-
-
-
-
13
-
-
-
-
-
-
14
-
-
-
-
-
-
Description :
+ : Found growth of microorganisms
– : Not found growth of microorganisms
Table 7. Antimicrobial Activity Assays
Formula
-tions
Zone of Inhibition (cm)
Staphylococcus aureus
Zone of Inhibition (cm)
Pseudomonas aeruginosa
A
Eff.
%
B
Eff.
%
C
Eff.
%
A
Eff.
%
B
Eff.
%
C
Eff.
%
1
5.06 +
0.115
5.13 +
0.040
5.09 +
0.025
5.13 +
0.006
5.05 +
0.035
5.09 +
0.06
2
4.98 +
0.085
5.02 +
0.080
5.00 +
0.025
5.10 +
0.038
5.10 +
0.095
5.1 +
0.03
3
4.93 +
0.068
5.08 +
0.145
5.06 +
0.025
5.06 +
0.020
5.02 +
0.02
5.06 +
0.035
Avr
4.99 +
0.064
91.14
5.08 +
0.055
92.78
5.05 +
0.045
92.24
5.09 +
0.038
98.17
5.06 +
0.043
97.59
5.08 +
0.018
97.97
Std
5.475 + 0.175
5.185 + 0.025
Description : A : Hydrogel formulation with HPC C : Hydrogel formulation with
B : Hydrogel Formulation with HPMC mixed both HPC and HPMC
Eff. % : Efficacy in percentage Std : Standard solution pure of CFH 0.3%
= (Avr / Std) x 100%
Avr : Averages
4.7 In Vitro Release Studies
Upon analysis of the correlation coefficient
of the percentage of cumulative drug
release against a time function as found in
Table 8, it appears to have a different trend
between separate polymers and their
combined use. Hydrophilic polymers such
as cellulose derivatives generally provide a
model for the release of diffusion drugs
concerning transferring the doses from the
dosage form to the in vitro medium used
(Jain et al. 2008). In the use of a separate
polymer, the in vitro release profile of
formulation looks an ordinary drug from
within a hydrophilic matrix such as first-
order kinetics. But in both combinations,
the kinetics models transform to non-
Fickian transport mechanism as the
Korsmeyer-Peppas model. Show that the
amount of doses is maintained better in the
right combination. These results state that
drug release can be controlled by adjusting
to a mixture of both in a better composition.
137
Table 8. Kinetic parameters of in situ gel CFH Formulation
Formulations
Correlation Coefficient (R2)
Zero Order
First Order
Higuchi Model
Korsmeyer
Peppas Model
A
1
0.8937
0.9934
0.9682
0.9461
2
0.9122
0.9912
0.9793
0.9755
3
0.9255
0.9905
0.9816
0.9658
B
1
0.9111
0.9826
0.9836
0.9719
2
0.9177
0.9865
0.9847
0.9658
3
0.9115
0.9834
0.9811
0.9651
C
1
0.9762
0.9671
0.9883
0.9899
2
0.9757
0.9774
0.9880
0.9887
3
0.9644
0.9856
0.9858
0.9768
5. CONCLUSION
Overall the formulation developed has
fulfilled the requirement of eye drops
product as USP monograph. The designed
composition has shown the combination of
both cellulose polymer derivatives can
restrain drug doses better than each
polymer. Proven by the release kinetics of
the combination formulation was longer,
namely Korsmeyer-Peppas model.
6. CONFLICT OF INTEREST
There is no conflict of interest.
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