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Contact lenses with dual drug delivery for the treatment of bacterial
conjunctivitis

Article  in  International Journal of Pharmaceutics · June 2018

DOI: 10.1016/j.ijpharm.2018.06.059

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 International Journal of Pharmaceutics 548 (2018) 139–150

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Contact lenses with dual drug delivery for the treatment of bacterial T
conjunctivitis
⁎
Furqan A. Maulvia, , Sulabh S. Singhaniaa, Ankita R. Desaia, Manish R. Shuklaa,
Aniruddha S. Tannka, Ketan M. Rancha, Bhavin A. Vyasa, Dinesh O. Shahb,c,d,e
a
Maliba Pharmacy College, Uka Tarsadia University, Surat 394350, India
b
Shah-Schulman Center for Surface Science and Nanotechnology, Dharmsinh Desai University, Nadiad 387001, India
c
Department of Chemical Engineering, University of Florida, Gainesville, FL 32611, United States
d
Department of Anaesthesiology, University of Florida, Gainesville, FL 32611, United States
e
School of Earth and Environmental Sciences, Columbia University, New York, NY, United States

A R T I C LE I N FO A B S T R A C T

Keywords: Currently, bacterial conjunctivitis is treated by frequent administration of antibiotic eye drop solutions, which is
Moxifloxacin HCl tedious and patient noncompliant. Contact lenses could be ideal medical devices to sustain the release of oph-
Semi-circular ring implants thalmic drugs, but the incorporation of the latter can alter the optical and physical properties of the lenses. In
Contact lenses addition, many contact lens users have reported the pink eye syndrome, making them unsuitable as ocular
Conjunctivitis
medical devices. In the present study, we have designed a novel type of lenses containing semi-circular rings
In vivo release kinetic study
In vivo efficacy study
loaded with moxifloxacin HCl (a broad spectrum antibiotic) and hyaluronic acid (a comfort agent), respectively,
in order to treat bacterial conjunctivitis without altering the critical lens properties. The drug loaded rings were
implanted separately within the periphery of the contact lenses using the modified cast moulding technology.
The atomic force microscopy report showed an average roughness of 22.27 nm for the implant lens, which was
significantly lower in comparison to the marketed Freshlook® (116.27 nm) contact lens. The major amount of
moxifloxacin HCl was leached (68.16–74.55%) during the monomer extraction and wet sterilization (autoclave)
steps; hence the lenses were terminally sterilized by radiation and packaged under dry condition (dehydrated).
The in vitro release data showed release for moxifloxacin HCl and hyaluronic acid up to 96 h. The in vivo drug
release studies showed significant improvement [ > MIC for Staphylococcus aureus] in the drug residence time in
comparison to the eye drop therapy. The in vivo efficacy study in the staphylococcus aureus induced conjunctivitis
showed equivalent healing effect with the single implant contact lens in comparison to the frequent high dose
eye drop therapy. The study demonstrated the successful application of the implantation technology to co-
deliver moxifloxacin HCl and hyaluronic acid from the contact lenses for the extended period of time to treat
conjunctivitis.

1. Introduction
Conjunctivitis is a common cause of the red eye which affects > 6
million people in United States with all ages and socioeconomic classes
(Shields and Sloane, 1990; Smith and Waycaster, 2009). The disease is
characterized by the dilatation of the conjunctival vessels which results
in the hyperemia, chemosis, lid edema and the typical eye discharge
(Azari and Barney, 2013). The disease is treated with high and frequent
dose of the antibiotic eye drop solution (Sheikh and Hurwitz, 2001).
The eye drop therapy is very inefficient, due to very low drug residence
time in the tear fluid, which leads to poor ocular bioavailability (Tangri
and Khurana, 2011). The limited duration of action of the eye drop
requires frequent dosing which affect the patient routine life style
(Cronau et al., 2010). Therefore, a novel approach that improves the
drug residence time on the ocular tissue is needed to overcome the
limitations of the eye drop therapy.
The use of the therapeutic soft contact lenses could be a promising
approach to increase the drug residence time on the cornea to treat the
conjunctivitis (Maulvi et al., 2016; Huang et al., 2016; Busin and
Spitznas, 1988). In the last few decades, scientists have succeeded to
control the delivery of the drugs through the contact lenses using sev-
eral approaches like the soaking method, molecular imprinting, drug-
nanoparticles, drug-film, ion-ligand systems, supercritical fluid tech-
nology, etc. (Furqan et al., 2009; Ranch et al., 2017; Maulvi et al., 2017;

⁎
Corresponding author.
E-mail address: furqanmpc@gmail.com (F.A. Maulvi).

https://doi.org/10.1016/j.ijpharm.2018.06.059
Received 17 March 2018; Received in revised form 26 June 2018; Accepted 26 June 2018
Available online 28 June 2018
0378-5173/ © 2018 Elsevier B.V. All rights reserved.
F.A. Maulvi et al. International Journal of Pharmaceutics 548 (2018) 139–150

Maulvi et al., 2015; Hsu et al., 2014; Carvalho et al., 2015; Xinming Table 1
et al., 2008). Phan et al. (2016) soaked the conventional and silicon Details of the composition of the base contact lens and implants.
contact lenses in the moxifloxacin solution for 24 h, and observed the Ingredients Base contact MOX-I-50 MOX-I-100 MOX-I-150 HA
sustained drug release up to 24 h (Phan et al., 2016). Jones and Hui lens
(2013) loaded ciprofloxacin and dexamethasone in the contact lenses
Moxifloxacin HCl – 50 mg 100 mg 150 mg –
by soaking method using acetate buffer with cyclodextrins and found
Hyaluronic acid – – – – 10 mg
high burst release (Jones and Hui, 2013). Bajgrowicz et al. (2015) HEMA 973 µl 940 µl 940 µl 940 µl 973 µl
loaded ciprofloxacin and moxifloxacin in the daily disposable contact Irgacure D 5 mg 20 mg 20 mg 20 mg 5 mg
lenses and found the high burst release reaching a plateau state within EGDMA 10 µl 10 µl 10 µl 10 µl 10 µl
15 min (Bajgrowicz et al., 2015), similar results were also observed by MAA 16.5 µl 20 µl 20 µl 20 µl 16.5 µl
Tween 20 – 100 µl 200 µl 300 µl 40 µl
Phan et al. (2016) for the fluconazole (Phan et al., 2016). The high
Water – 100 µl 100 µl 100 µl –
initial burst release with steep decline in the drug release profile of the
contact lenses prepared using soaking method make this technique
unsuitable for drug loading. (18.2 MΩ cm) was obtained from synergy U.V. Millipore water pur-
To treat the allergic conjunctivitis, González-Chomón et al. (2016) ification system. All other reagents were purchased from Sigma-Aldrich
developed the biomimetic contact lenses using acrylic acid, 2-acryla- Chemicals (MO, USA).
mido-2-methyl-1-propane-sulfonic acid and benzyl-methacrylate as
functional monomers. The lenses showed sustained release up to 24 h,
2.2. Formulation development
inhibiting the response of the sensitized mast cells (González-Chomón
et al., 2016). Negin (Malakooti et al., 2015) incorporated the functional
2.2.1. Fabrication of the drug-loaded semi-circular rings/implants
monomers and applied the molecular imprinting technology to load
The antibiotic-loaded implants were fabricated at three different
polymyxin B and vancomycin (Malakooti et al., 2015). However, the
concentration of the moxifloxacin HCl, as shown in the Table 1. The
high degree of cross linking in the molecular imprinting can alter the
40 µm thickness implants were prepared by the free radical poly-
optical and physical characteristics of the contact lenses. Paradiso et al.
merization technique using the monomer mixtures. The composition of
(2016) incorporated vitamin E as a diffusional barrier to extend the
the monomer mixture for the base contact lens and the drug-loaded
release of levofloxacin and chlorhexidine from the 1-DAY ACUVUE®
implants are shown in the Table 1.
and ACUVUE OASYS® contact lenses (Paradiso et al., 2016). The sig-
The required quantity of the moxifloxacin HCl was added in the
nificant reduction in the water content of the silicone contact lenses was
mixture of water and Tween 20, followed by the addition of other in-
observed by incorporating vitamin E in an attempt to extend the release
gredients like HEMA, MAA, EGDMA and Irgacure D. The drug-laden
of ciprofloxacin and betamethasone (Rad and Mohajeri, 2017; Rad and
monomer mixture was sonicated for 15 min to remove the air bubbles.
Mohajeri, 2016). Guzman et al. (2017) developed the multi-layer con-
The mixture was then poured into the glass moulds which were sepa-
tact lenses with drug layer sandwiched between vitamin E as the barrier
rated by Teflon spacer of 40 μm. The mould was then shifted to the
layers. The Quasi-Case II non-Fickian controlled diffusion release was
Ultraviolet transilluminiator cabinet and the sheet was polymerized at
achieved for 30 h, with no burst release (Guzman et al., 2017). Qin et al.
360–370 nm for 45 min. The drug-laden sheet was then punched using
(2017) developed the contact lenses loaded with the fluorous-tagged
the metal borer to get a circular ring with 6 mm inner diameter and
ciprofloxacin which shows the excellent antimicrobial activity against
8 mm outer diameter. The circular ring was further carefully cut into
the pseudomonas aeruginosa (Qin et al., 2017). While these approaches
the two equal parts from the center using the cutter to get a semi-cir-
have demonstrated the contact lenses as an ideal medical device to
cular ring/implant of 2.1 ± 0.3 mg (Fig. 1). Similarly, the HA-laden
control the release of ophthalmic drugs in the treatment of con-
semi-circular rings/implants of 2.1 ± 0.2 mg was fabricated using the
junctivitis, but the method of incorporation of drug/formulation have
free radical polymerization technique, with the curing time of 30 min
altered the optical and physical properties of the contact lenses (Maulvi
(Maulvi et al., 2017). The semi-circular rings were stored in the de-
et al., 2016; Gulsen and Chauhan, 2004; Guzman-Aranguez et al.,
siccators (45% relative humidity) at room temperature till further use.
2013). Also, many contact lens users have reported the pink eye syn-
drome at the end of the day making it unsuitable to be accepted as the
medical device (Chynn et al., 1995; Schein et al., 1989). 2.2.2. Implantation of the drug-loaded semi-circular rings/implants in the
In the present study, we have designed a novel moxifloxacin HCl contact lenses
and hyaluronic acid (HA) loaded semi-circular acrylate rings which The dual implant contact lens (14.2 mm outer diameter and 6.5 mm
were implanted separately within the periphery of the hydrogel contact base curve) was fabricated by the modified cast moulding method. As
lenses using the modified cast moulding technology (Desai et al., 2018). shown in Fig. 1, moxifloxacin HCl-implant and HA-implant was placed
The objective was to treat the conjunctivitis and to provide the comfort in the female mould (polypropylene mould) keeping a distance of 6 mm
to the patient’s eye with the dual delivery of antibiotic (moxifloxacin from the center, followed by the addition of the excess amount of the
HCl) and comfort enhancing agent (HA) from the single implant contact monomer mixture (base contact lens monomer solution, Table 1). The
lens. Thus the implant contact lenses could improve the patient ad- male and female moulds were aligned and they were cured by exposing
herence to the therapy and thus can lead to better clinical outcomes for to UV transilluminiator at 360–370 nm for 1 h. The dual implant con-
the treatment of conjunctivitis. tact lenses were removed and preserved at the room temperature in the
desiccator (45% relative humidity). The optical transparency of the
2. Materials and methods implant contact lens was not altered as the semi-circular rings/implants
were placed towards the outer periphery of the contact lens leaving a
2.1. Materials region of 6 mm diameter from the center for clear vision. The implant
contact lenses were coded as MOX-HA-I-50-CL, MOX-HA-I-100-CL and
Hydroxylethylmethacrylate (HEMA), methacrylic acid (MAA), MOX-HA-I-150-CL for the respectively implants as shown in Table 1.
Irgacure® (1-Hydroxycyclohexyl phenyl ketone), ethylene glycol di-
methacrylate (EGDMA), StainAll dye, Tetra butyl ammonium hydrogen 2.2.3. Moxifloxacin HCl and HA-laden contact lenses prepared by soaking
sulfate and Triethylamine were purchased from Sigma-Aldrich method
Chemicals (St. Louis, MO, USA). Hyaluronic acid was purchased from The experiment was performed to compare the semi-circular rings
Shandong Runxin Biotechnology Co., Ltd (China). Ultrapure water implant contact lenses with the soaked contact lenses. Moxifloxacin HCl

140
F.A. Maulvi et al.
Fig. 1. Illustration of fabricating moxifloxacin HCl and HA-loaded semi-circular
rings implanted contact lenses using the modified cast moulding technique. (A)
Moxifloxacin HCl loaded implant, (B) HA loaded implant, (C) Top view image
of mould showing position of implants. (D) Final fabricated (100 µm thickness)
contact lens showing 6 mm centre aperture and semi-circular rings. Semi-cir-
cular ring 1 (opaque, moxifloxacin HCl loaded ring): Blue arrow points to the
inner margin of the ring and brown arrow point’s outer margin. Semi-circular
ring 2 (transparent, Hyaluronic acid loaded ring): Pink arrow points to the inner
margin of the ring and white arrow point’s outer margin.
and HA was loaded into the contact lenses (fabricated using base con-
tact lens monomer mixture and processed to remove unreacted
monomer according to Section 2.3.4) by soaking in the simulated tear
fluid (STF, pH 7.4, osmolarity = 295.7 mosmoles/L, 2 ml, prepared by
dissolving 0.9% w/v sodium chloride, and 0.015% w/v sodium bi-
carbonate in de-ionized water) containing a fixed strength of 0.15% w/
v HA (Maulvi et al., 2015) and varying the concentration of the mox-
ifloxacin HCl (1 mg/ml, 3 mg/ml, and 5 mg/ml coded as MOX-HA-SM-
1, MOX-HA-SM-3, and MOX-HA-SM-5 respectively). The contact lenses
were then autoclaved (121 °C, 15 psi for 30 min) and thereafter soaked
for a period of 48 h in solutions of different concentration as reported
above. After soaking, the contact lenses were removed and carefully
blotted to remove the excess of the soaking solution from the surface of
the contact lenses and were then subjected for characterization (Kim
and Chauhan, 2008). The soaking solutions were analyzed to calculate
the uptake of moxifloxacin HCl and HA by a developed and validated
HPLC method at 293 nm (Respaud and Grayo, 2012) and by the col-
orimetry method (using StainAll dye) at 640 nm (Fagnola et al., 2009;
Homer et al., 1993) respectively.
2.2.4. Terminal sterilization
Mostly the contact lenses sterilized by the autoclaving method (wet
process) have very high chances of the drug leaching, especially with
the water soluble drugs like moxifloxacin HCl. The implant contact
lenses [MOX-HA-I-50-CL, MOX-HA-I-100-CL and MOX-HA-I-150-CL]
were sterilized using autoclave (121 °C, 15 psi and 30 min) in 2 ml of
the STF. After sterilization, the STF was analyzed for the moxifloxacin
HCl and HA content to calculate the percentage leaching of the drugs
from the implant contact lenses (Maulvi et al., 2017). All readings were
recorded in triplicate.
In another set, the implant contact lenses were sterilized by UV
radiation sterilization technique using the UV-B lamp (G6T5E, Sankyo
Denki Co. Ltd., Japan) at 290–310 nm applying 500 mW/cm2 for
180 min (Gritz et al., 1990).
141
International Journal of Pharmaceutics 548 (2018) 139–150
2.3. Characterization of the hydrogel contact lenses
2.3.1. Swelling study
The weight of the dry contact lens (WD) after removing from the
mould and after 24 h of wetting in the simulated tear fluid (WS) was
measured at 37 °C (Maulvi et al., 2014; Jung et al., 2013). The per-
centage swelling of each batch was then calculated as follows:
WS−WD
% Swelling = × 100
WD
2.3.2. Optical transparency
The optical transparency of the therapeutic contact lenses should
not be affected due to the presence of the drug or the drug loaded
formulation. Any alteration in the transparency of the contact lens
would directly hinder the vision of the contact lens user. The optical
transparency of the soaked and implanted contact lenses was de-
termined by UV–vis spectrophotometer. The contact lenses were hy-
drated by soaking it in the simulated tear fluid for an overnight. This
hydrated contact lens was carefully cut in to a small 0.5 × 0.5 cm area
and mounted in the glass cuvette. The cuvette was placed in the UV–vis
spectrophotometer and the transmittance was measured at 630 nm
wavelength. All readings were recorded in triplicate.
2.3.3. Quantification of the drug loaded in the contact lenses
The soaked contact lenses and the MOX-implants were separately
transferred in the screw capped glass vials containing 25 ml of 10%v/v
aqueous methanolic solution. The vials were agitated at 100 rpm in the
incubator shaker for 10 days at 37 °C to extract the moxifloxacin HCl.
After 10 days, the solutions were analyzed for the moxifloxacin HCl
using HPLC at 293 nm after appropriate dilution. Similarly, to quantify
HA the soaked contact lens and HA-implants were separately trans-
ferred in the glass vial containing 25 ml of distilled water. The HA was
quantified by the developed and validated colorimetric method
(Fagnola et al., 2009; Homer et al., 1993) using Stain-All dye after
suitable dilution at 640 nm. All readings were recorded in triplicate.
2.3.4. Removal of unreacted monomers from the implant contact lenses
To remove the un-reacted monomers left after the curing process,
the implant contact lenses were individually placed in the 5 ml of
boiling water for 15 min (Alvarez Lorenzo et al., 2002; Andrade Vivero
et al., 2007). The amount of moxifloxacin HCl and HA leached out in
the water was quantified by the HPLC and colorimetric method re-
spectively. All readings were recorded in triplicate.
2.4. Atomic force microscopy (AFM)
AFM is a very powerful tool to analyze the surface topography and
to compare the hydrated surface of the contact lenses on the numerical
basis (Guryca et al., 2007). The method avoids the artefacts due to the
dehydration which can occur with low voltage scanning electron mi-
croscopy (SEM). The marketed contact lens (Freshlook One Day Color
Contact Lens by Alcon) and the implant contact lens [batch MOX-HA-I-
150-CL] were evaluated for the surface morphology. The
25 µm × 25 µm area was analyzed at three different locations in the
surface tapping mode and the average surface roughness was calculated
by the inbuilt software in Atomic Force Microscope (AFM) – NT-MDT
(Model No: NT MDT NTEGRA Prima, USA). The implant area was
analyzed in case of the implant contact lens. The AFM consists of a
micro scale cantilever with a sharp tip (probe) that is used to scan the
specimen surface. The cantilever is typically made of silicon or silicon
nitride with a tip radius of curvature of the order of nanometers. When
the tip is brought into the proximity of a sample surface, forces between
the tip and the sample cause the cantilever to deflect according to the
Hooke law. All images were collected in the height mode, which keeps
the force constant (Lira et al., 2008; Giraldez et al., 2010).
F.A. Maulvi et al. International Journal of Pharmaceutics 548 (2018) 139–150

2.5. In vitro release study
The in vitro release study of the soaked contact lenses, implant
contact lenses (wet sterilized and radiation sterilized) and the semi-
circular implants (individually without autoclave) were carried out by
immersing them separately in 2 ml of STF at 34 °C with constant stirring
in the incubator shaker at 100 RPM (Maulvi et al., 2017; Maulvi et al.,
2016; Ciolino et al., 2009). The 2 ml of STF was then completely dec-
anted and superseded by the fresh STF at the pre-established time in-
tervals to mimic the in vivo sink condition. The amount of the moxi-
floxacin HCl and HA released was quantified using HPLC at 293 nm and
UV spectrophotometer at 640 nm (colorimetric method) respectively.
The sampling was carried out until there was no increase in the drug
concentration in 2 successive measurements. The studies were carried
out six times (n = 6).
2.6. Animal studies
All animal studies were performed with prior approval from the
Institutional Animal Ethical Committee (IAEC) (Protocol No: MPC/
IAEC/11/2017) of Maliba Pharmacy College, Bardoli, India. The in vivo
studies were designed according to the guidelines of the CPCSEA
(Committee for the Purpose of Control and Supervision of Experiment
on Animals). New Zealand white rabbits of either sex weighing between
3.8 and 4.2 kg were housed individually in stainless steel cages in a
light controlled room at 20 ± 1 °C with no restriction of food and
water intake.
• Group 4: Conjunctivitis was induced and treated with implant
contact lenses (MOX-HA-I-150-CL, 148 µg loading of MOX, Test
group).
In this study, the group 1 rabbits were caged and neither the con-
junctivitis was induced nor they were treated with any of the for-
mulation; while the conjunctivitis was induced in both the eyes of
group 2–4 using the young culture of the Staphylococcus aureus. The
50 µl of culture solution (102 CFU in 10 µl of tryptic soy broth
(O’Callaghan, 2018) was gently instilled in the lower conjunctival sac of
the rabbit eye and holded for few seconds to ensure the uniform
spearing of the bacteria. After 48 h, the rabbits’ eyes showed the
symptoms of discharge, chemosis, conjunctival congestion and pal-
pebral fissure, indicating the successful induction of the conjunctivitis.
The treatment was started from the day 3, i.e. after successful induction
of conjunctivitis. In group 2, the rabbit’s eyes were treated with one
drop of the sterile saline solution every 4 h, which served as the nega-
tive control group. In the group 3 (positive control group), rabbit’s eyes
were treated with one drop of the moxifloxacin HCl eye drop solution
(0.5% w/v) in 4 h interval. The radiation sterilized implant contact
lenses (MOX-HA-I-150-CL, 148 µg loading of MOX) were carefully
placed on the cornea of the group 4 (test group) without anaesthesia.
The rabbits were kept under observation and symptoms like the dis-
charge, chemosis, conjunctival congestion and palpebral fissure were
observed and scored at every 12 h (Table 2) (Wahaab et al., 2015). The
treatment was conducted for 4 days after the induction of the con-
junctivitis.

2.6.1. In-vivo drug release study 2.7. Statistical analysis

The in-vivo drug release study was conducted to assess the amount
of moxifloxacin HCl released from the implant contact lenses (MOX-HA- Statistical analysis was carried out using the SPSS 21.0 for Windows.
I-150-CL, 148 µg loading of MOX) in the rabbit tear fluid in comparison The t-test (2 tailed) and one-way analysis of variance (ANOVA) was
to 0.5 %w/v moxifloxacin HCl eye drop therapy (1 drop = 250 µg used to compare the different groups, after confirming the normality
moxifloxacin HCl) (Maulvi et al., 2016; Chhonker et al., 2015). The and homogeneity of variance.
radiation sterilized moxifloxacin HCl implant contact lenses were
gently placed on the rabbit cornea (right eye) without anaesthesia with
3. Results and discussion
utmost care (n = 6 rabbits, left eye control). At the specified time in-
tervals, 60 μl of the saline solution (0.9% NaCl) was instilled in the
3.1. Characterization of the contact lenses
lower conjunctival sac of the right eye and after 5 s maximum tear fluid
was collected using micropipette (10–100 µl capacity) in a pre-weighed
3.1.1. Swelling study
eppendorf tube. The collected tear fluids were treated with 1 ml of
The percentage swelling (water content) is one of the critical
methanol to precipitate out the biological proteins, followed by the
parameter that decides the wearable fate of the contact lens and the
centrifugation for 15 min (freeze centrifuge, 10,000 RPM). The super-
swelling capacity majorly depend upon the materials (monomers) from
natant was collected and analyzed for the moxifloxacin HCl content
using LC–MS (TSQ Quantum Access, Thermo Scientific, USA). The
Table 2
measured moxifloxacin HCl concentration in the tear fluid was plotted Scoring of the ocular inflammation based on the conjunctivitis symptoms.
against time and compared with the single topical moxifloxacin HCl eye
Observations Scoring of the ocular inflammation Scores
drop instillation (0.5% w/v MOXIZEE).
Mucopurulent No discharge 0
2.6.2. Efficacy study discharge Minimal discharge 1
The efficacy of the implant contact lenses were evaluated using the Sticking of the eyelids with discharge 2
New Zealand white rabbits, and was compared with the conventional Hair around the eye wetted with discharge 3
and surrounding skin area inflammation
eye drop therapy. The conjunctivitis was induced using young culture
of the Staphylococcus aureus (ATCC 25923, 100 CFU/ml) (Ilechie et al., Chemosis No chemosis 0
Minimal edema of the conjunctiva 1
2012). Rabbits’ eyes were examined using portable slit lamp prior to the
Obvious conjunctival edema with eversion of 2
induction of the conjunctivitis to exclude any abnormalities. The study eyelids
includes 4 groups (n = 6 rabbits in each group) and both the eyes of Conjunctival edema clearly visible even 3
rabbits were utilized for the study. without eversion of eyelids

Conjunctival No congestion 0
• Group 1: Uninfected and untreated (i.e. conjunctivitis was not in- Congestion Minimal congestion
Bright red conjunctiva
1
2
duced)
• Group 2: Conjunctivitis was induced and treated with sterile saline Palpebral fissure
Beefy red conjunctiva

Absent
3

0
(0.9%w/v NaCl) solution (Negative control).
• Group 3: Conjunctivitis was induced and treated with commercial Mild (lids are little puffy)
Moderate (swelling of upper and lower eyelid)
1
2
eye drop solution containing (0.5% w/v, MOXIZEE) moxifloxacin Severe (eyelids are swollen) 3
HCl (Positive control).

142
F.A. Maulvi et al. International Journal of Pharmaceutics 548 (2018) 139–150

Table 3
Swelling data of soaked contact lenses, implants and implant contact lenses. CL in code indicates contact lens. Values are shown as
mean ± standard deviations (n = 3).
Codes % Swelling [Mean ± SD] % Transmittance [Mean ± SD] at 630 nm

Control contact lens (CL) 83.96 ± 7.90 98.33 ± 2.96

MOX-HA-SM-1 CL 85.02 ± 4.59 93.63 ± 4.64
MOX-HA-SM-3 CL 87.63 ± 3.98 86.46 ± 5.42
MOX-HA-SM-5 CL 85.22 ± 4.49 82.57 ± 6.75

HA (Implant)* 86.32 ± 3.34 –

MOX-I-50 (Implant) 50.46 ± 4.05 –
MOX-I-100 (Implant) 48.03 ± 1.85 –
MOX-I-150 (Implant) 51.73 ± 7.33 –

MOX-HA-I-50-CL 72.54 ± 2.63 99.54 ± 1.04

MOX-HA-I-100-CL 75.53 ± 3.74 99.12 ± 1.32
MOX-HA-I-150-CL 70.42 ± 2.42 99.64 ± 1.54

*
HA implant is same for all three batches of implant contact lenses.

Table 4 showed significant decline (p < 0.01) in the swelling behavior, which
The drug loading data for the soaked contact lenses and the implants. Values is generally not preferred as it can change the shape of the contact lens
are shown as mean ± standard deviations (n = 3). (Pinchuk et al., 1984). Although significant distortion in the shapes of
Code Drug loaded in the lenses and implant (µg) the final fabricated contact lenses were not observed. The HA-loaded
implants did not show any significant change (p > 0.05) in the %
Moxifloxacin HCl Hyaluronic acid (HA) swelling in comparison to the control contact lenses. The final implant
contact lenses did show reduction in % swelling, which suggests the
MOX-HA-SM-1 72.04 ± 10.26 07.90 ± 0.96
MOX-HA-SM-3 529.67 ± 39.47 08.10 ± 0.52 tailoring of the monomer composition of implants in future clinical
MOX-HA-SM-5 931.71 ± 66.11 07.48 ± 0.35 studies.
MOX-HA-I-50 implant 68.73 ± 9.12 17.92 ± 2.01
MOX-HA-I-100 implant 101.90 ± 3.31 18.01 ± 2.51 3.1.2. Optical transparency
MOX-HA-I-150 implant 148.06 ± 12.30 18.65 ± 1.94
The % transmittance value should be greater than 95% for the
contact lens to provide an unhindered clear vision to the users. The
blank contact lenses when soaked in the different concentrations of the
Table 5
moxifloxacin HCl, the optical transparency of the soaked contact lenses
Data of Moxifloxacin HCl and HA leached during monomer extraction
(Mean ± SD, n = 3). (after 48 h) decreased significantly (p < 0.05) with an increase in the
concentration of the moxifloxacin HCl in the soaking solution (Table 3).
Code Moxifloxacin HCl HA
This was due to inherent characteristics of the moxifloxacin HCl which
µg (%) µg (%)
shows yellow color. Thus the soaking method was not preferred for the
colored drugs like the moxifloxacin HCl. While the implant contact
MOX-HA-I-50-CL 19.78 ± 2.34 28.77 ± 3.40 0.72 ± 0.15 4.01 ± 0.84 lenses did not show reduction in the optical transparency, which was
MOX-HA-I-100- 27.65 ± 1.47 27.13 ± 1.44 0.62 ± 0.20 3.45 ± 1.11 expected since the implants/rings were placed towards the outer per-
CL
MOX-HA-I-150- 39.23 ± 8.27 26.34 ± 5.55 0.71 ± 0.16 3.80 ± 0.86
iphery of the contact lens leaving a region of 6 mm diameter from the
CL center, as shown in Fig. 1. Hence this technology can be an outbreak for
the delivery of coloured compounds via contact lenses.

Table 6 3.1.3. Quantification of the drug loaded in the contact lenses

Leaching data of Moxifloxacin HCl and HA during the sterilization step
The soaked contact lenses and the implants were evaluated for the
(Mean ± SD, n = 3).
uniform dispersion of the drugs in the contact lens and the reproduci-
Code Moxifloxacin HCl HA bility of the fabrication process. The drug loaded values for the soaked
contact lenses and the implants are shown in the Table 4. As expected,
µg (%) µg (%)
the results of the soaked contact lenses indicate that as the concentra-
MOX-HA-I- 28.44 ± 02.89 41.39 ± 04.20 00.58 ± 00.23 3.26 ± 1.29 tion of the moxifloxacin HCl in the soaking solution increases, pro-
50-CL portionally the drug loading also increased. The high standard devia-
MOX-HA-I- 47.70 ± 10.80 46.81 ± 10.59 00.65 ± 00.15 3.65 ± 0.84 tion values suggest poor reproducibility of the soaking method to load
100-CL
MOX-HA-I- 61.69 ± 07.68 41.66 ± 05.18 00.80 ± 00.35 4.29 ± 1.89
the drug. The reasons for the deviations could be the uneven drug
150-CL precipitation or drug adsorption onto the side of the vial. Also the
concentrations of the drug-loading solutions were many folds higher
than the amount of drug uptake in the lens, giving rise to error in the
which they have been fabricated. In the present work, we have used the measurements.
p-HEMA based monomers for fabricating the contact lenses and the The uptake of HA from the soaking solution (0.15% w/v HA;
implants, which have acceptable water retention capability for the common for all three batches) was found to be in the range of
comfort wear. 7.48 ± 0.35 to 8.10 ± 0.52 µg. The low uptake values indicate that
The soaked contact lenses showed an insignificant (p > 0.01) the HA was adsorbed only on to the surface of the contact lens, with no
changes/alterations in % swelling in comparison to the control contact penetration inside the matrix structure, owing to its high molecular
lenses (Table 3). The results indicate that the presence of the hydro- weight (Maulvi et al., 2017).
philic drugs (moxifloxacin HCl and HA) did not alter the swelling be- The drug loaded values of the moxifloxacin HCl and HA implants
havior of the contact lenses. The moxifloxacin HCl loaded implants were in the range of 68.73 ± 9.12 to 148.06 ± 12.30 µg and

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F.A. Maulvi et al. International Journal of Pharmaceutics 548 (2018) 139–150

Fig. 2. Three-dimensional image of the surface topography generated by the AFM analysis of the Freshlook One Day Color Contact Lenses by Alcon and the implant
contact lens [batch MOX-HA-I-150-CL].

Fig. 3. Cumulative release (μg) of moxifloxacin HCl-laden soaked contact

lenses. The total amount of moxifloxacin HCl released from the soaked contact
lenses are 62.61 ± 02.07, 398.06 ± 36.51 and 782.58 ± 11.36 μg from
MOX-HA-SM-1, MOX-HA-SM-3, and MOX-HA-SM-5 batches respectively.
Values are shown as mean ± standard deviations (n = 6).
Fig. 5. Cumulative release (µg) of HA from the soaked contact lenses (MOX-HA-
SM-5) and implant contact lenses (MOX-HA-I-150). Values are shown as
mean ± standard deviations (n = 6). The release profile of MOX-HA-SM-1 and
MOX-HA-SM-3 are not shown, as it was similar to MOX-HA-SM-5, due to the
same strength of HA soaking concentration in all three batches.

Fig. 6. Release rate (ng/h) of HA from the soaked contact lenses (MOX-HA-SM-
5) and implant contact lenses (MOX-HA-I-150). Values are shown as mean ±
Fig. 4. Release rate (ng/h) of moxifloxacin HCl from the soaked contact lenses.
standard deviations (n = 6).
Values are shown as mean ± standard deviations (n = 6).

3.1.4. Removal of unreacted monomers from implant contact lenses

17.92 ± 2.01 to 18.65 ± 1.94 µg respectively. According to the re-
The implant contact lenses were fabricated by free radical poly-
ported literature calculations (Phan et al., 2016), moxifloxacin HCl
merization technique, so it was necessary to remove the un-reacted
loading in the implant was sufficient to treat the conjunctivitis, how-
monomers from the hydrogel matrix. The percentage loss of moxi-
ever the system should show sustained release for at least 3 days. The
floxacin HCl and HA during the monomer extraction in 5 ml of boiling
low standard deviation values (implants) suggest the reproducibility
water are shown in the Table 5. The results showed that 26.34 ± 5.555
and reflect the suitability of the implant fabrication process. The results
to 28.77 ± 3.40% of the moxifloxacin HCl and 3.80 ± 0.86 to
also confirmed no degradation of the drugs during the fabrication
4.01 ± 0.84% of the HA were leached out during the monomer ex-
process.
traction step. Moxifloxacin HCl is water soluble drug, thus high
leaching was expected. While HA implant showed < 5% of leaching,

144
F.A. Maulvi et al.
Fig. 7. Cumulative release (μg) of moxifloxacin HCl from the implant contact
lenses post monomer extraction and sterilization. The cumulative amount of
moxifloxacin HCl released from the implant contact lenses are 5.12 ± 01.07,
16.07 ± 03.82 and 20.25 ± 02.11 from MOX-HA-I-50-CL, MOX-HA-I-100-CL,
and MOX-HA-I-150-CL batches respectively. Values are shown as mean ±
standard deviations (n = 6).
Fig. 8. Release rate (ng/h) of moxifloxacin HCl from the implant contact lenses
post monomer extraction and sterilization. Values are shown as mean ±
standard deviations (n = 6).
Fig. 9. Cumulative release (μg) of moxifloxacin HCl from the implant contact
lenses (radiation sterilized). The cumulative amount of moxifloxacin HCl re-
leased from the implant contact lenses were 50.99 ± 10.25, 97.67 ± 05.60
and 143.41 ± 09.02 µg from MOX-HA-I-50-CL, MOX-HA-I-100-CL, and MOX-
HA-I-150-CL batches respectively. The cumulative amount of moxifloxacin HCl
released from the implants (radiation sterilized) were 53.70 ± 03.26,
82.38 ± 11.74 and 131.99 ± 12.56 µg from MOX-I-50, MOX-I-100, MOX-I-
150, respectively. Values are shown as mean ± standard deviations (n = 6).
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International Journal of Pharmaceutics 548 (2018) 139–150
Fig. 10. Release rate (ng/h) of moxifloxacin HCl from the implant contact
lenses (radiation sterilized) and from the implants. Values are shown as
mean ± standard deviations (n = 6).
Fig. 11. Moxifloxacin HCl tear fluid concentration-time profile after application
of 24 h hydrated radiation sterilized implant contact lenses (MOX-HA-I-150 CL,
148.06 ± 12.30 µg loading) and the single instillation of moxifloxacin HCl eye
drop (50 µl = 250 µg of moxifloxacin HCl). Each points represents the
mean ± standard deviations (n = 6). The inset shows the initial 2 h release
profile. Minimum inhibitory concentration (MIC) of moxifloxacin HCl for
Staphylococcus aureus = 4 µg/ml.
owing to its long polymeric chain structure and high molecular weight.
3.1.5. Effect of terminal sterilization
The contact lenses were sterilized to prevent the eye irritation and
infection which may lead to patient non-compliance. The amount of
moxifloxacin HCl and HA leached out/lost during the sterilization of
the implant contact lenses are shown in Table 6. Leaching of the
moxifloxacin HCl from the implant contact lenses was 41.39 ± 04.20
to 46.81 ± 10.59%, while only 3.26 ± 1.29 to 4.29 ± 1.89% of the
HA was lost during the sterilization step. The results are obvious as
discussed in the monomer extraction step.
The prevention of drug loss during the wet sterilization process
(autoclaving) has been a challenging task for the researchers. In our
previous work (Maulvi et al., 2017), we have addressed this critical
issue using the pH sensitive Eudragit S100 nanoparticles. This concept
worked with only low dose (potent) drugs like cyclosporine, bimato-
prost, etc. In case of the moxifloxacin HCl, high dose was required to be
loaded in the contact lenses, which would add the huge mass of the
F.A. Maulvi et al. International Journal of Pharmaceutics 548 (2018) 139–150

Fig. 12. High-performance liquid chromatography–mass spectrometry (LC–MS) of Moxifloxacin HCl sample. Tear sample containing Moxifloxacin HCl released from
the implant contact lenses demonstrated ion chromatograms and annotated high-resolution mass spectra (A) that were substantially similar to those of pure com-
mercial Moxifloxacin HCl (B). The mass spectra of both the samples generated the same fragmentation pattern of the protonated ion [MOX þ H] þ at m/z 402.2 for
MOX. m/z = mass to charge ratio.

polymeric material affecting the physical properties of the implants and
the contact lenses. Therefore, the implant contact lenses were not
preferred to be supplied in the hydrated state (i.e. after moist ster-
ilization). Thus, the option of sterilizing the implant contact lenses in
dry state using radiation sterilization technique, followed by the
packaging under the aseptic condition will overcome the problem of
drug loss under the hydrated conditions.
3.2. Atomic force microscopy (AFM)
The AFM was used to evaluate the alterations in the surface
smoothness of the contact lenses, due to the implantation of the HA and
the Moxifloxacin HCl. The AFM report of Freshlook contact lens
(marketed by Alcon) and implant contact lens (MOX-HA-I-150 CL) are
shown in Fig. 2. The average roughness of the Freshlook contact lens
was found to be 116.07 nm, while the implant contact lens showed
comparatively much lower value of 22.27 nm, suggesting the comfort
wear for users. In the literature, Vilem Guryca (Guryca et al., 2007)
visualized the surface roughness of various market contact lenses, with
average surface roughness was in the range of 0.7–18.8 nm. Also, the
similar study was conducted by Giraldez et al. (2010), where the
average surface roughness of various marketed contact lenses ranged
between 2.34 nm and 12.99 nm.
The presence of the moxifloxacin HCl and the HA implants did not
affect the surface smoothness of the contact lenses, instead it was much
smoother then the marketed cosmetic contact lens. Thus the contact
lenses fabricated by the implantation technology will outweigh the
discomfort caused by the conventional contact lens wear which will
prompt easy and comfort wear.

146
F.A. Maulvi et al.
Fig. 13. Clinical score of conjunctivitis; (Group 1) Uninfected and untreated,
(Group 2) Conjunctivitis was induced and treated with saline solution (Negative
control), (Group 3) Conjunctivitis was induced and treated with commercial
eye drop solution containing (0.5% w/v) moxifloxacin HCl (Positive control),
(Group 4) Conjunctivitis was induced and treated with the implant contact
lenses (Test group). The treatment was started on day 3 (72 h) in the group 2, 3
and 4.
3.3. In vitro release study
3.3.1. In vitro release of moxifloxacin HCl and HA from the soaked contact
lenses
The cumulative release (µg) and release rate (ng/h) profiles are
presented in Figs. 3 and 4 respectively. During the soaking period of
48 h, the uptake of moxifloxacin HCl by the contact lenses were found
to be 72 ± 07, 529 ± 24 and 931 ± 75 µg for batch MOX-HA-SM-1,
MOX-HA-SM-3 and MOX-HA-SM-5 respectively. The in vitro release
data showed the high initial burst release (> 80%) of moxifloxacin HCl,
which indicates the release of adsorbed drug from the contact lenses,
followed by the rapid decline in the drug release rate. The results
suggest the drawback of the soaking method for water soluble drug
moxifloxacin HCl. The drug release profiles of the different batches
showed increase in the drug release rate with increase in the drug
loading amount (MOX-HA-SM-5 > MOX-HA-SM-3 > MOX-HA-SM-
1), while the pattern of drug release rate remained the same. The drug
was detected in the HPLC till 72 h, 72 h and 96 h for MOX-HA-SM-1,
MOX- HA-SM-3 and MOX-HA-SM-5 batches respectively. However the
batches MOX-HA-SM-3 and MOX-HA-SM-5 cannot be used for the
therapeutic purpose, as the optical transmittance values were lower
than 90% (Table 3). The cumulative amount of moxifloxacin released
from the soaked contact lenses were lower than the uptake values,
which indicate that some part of the drug is either permanently en-
trapped inside the matrix of the contact lens or was not detectable on
HPLC. The other reason for the difference could be the error in the
measurements of the drug uptake values, as the concentrations of the
drug-loading solutions were many folds higher than the amount of drug
loaded in the lenses.
Similarly, the high initial burst release of HA was observed from the
soaked contact lenses (for all three batches), with the cumulative re-
lease of 6.48 ± 0.35 μg (Figs. 5 and 6). The results are obvious, be-
cause the HA has high molecular weight which restricts its entry into
the aqueous channels of the contact lenses and gets adsorbed only on
the surface, which released rapidly in flux media (Maulvi et al., 2017).
3.3.2. In vitro release of moxifloxacin HCl and HA from the implant contact
lenses after monomer extraction and wet sterilization
The implant contact lenses were treated for the monomer extraction
and the wet sterilization steps (autoclave) prior to the in vitro release
study. The total amount of the moxifloxacin HCl leached during the
above treatment was 48.22 µg (70.15%), 75.35 µg (74.55%) and
100.92 µg (68.16%) for MOX-HA-I-50-CL, MOX-HA-I-100-CL and MOX-
HA-I-150-CL batches respectively (Tables 5 and 6). The results showed
that the major amount of the moxifloxacin HCl was lost during the
monomer extraction and the wet sterilization steps. The lenses after
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International Journal of Pharmaceutics 548 (2018) 139–150
treatment were shifted to the in vitro release study where the cumula-
tive moxifloxacin HCl released was found to be 5.12 µg, 16.07 µg and
20.25 µg for MOX-HA-I-50-CL, MOX-HA-I-100-CL and MOX-HA-I-150-
CL batches respectively. The cumulative release (µg) and release rate
(ng/h) profiles of the implant contact lenses post monomer extraction
and sterilization are presented in the Figs. 5 and 6 for HA and Figs. 7
and 8 for moxifloxacin HCl respectively.
The system showed dual phase release pattern, initially there was a
burst release (desired in case of antibiotics to kill the microorganism) of
the moxifloxacin HCl from the aqueous channels of the contact lens and
the implant matrix, followed by the extended release of tightly bound
drug from the implant matrix (from 72 h to 96 h), due to the drug-
polymer interactions. Thus, even with the low drug loading in com-
parison to the high drug-loaded soaked contact lenses, the implant
moxifloxacin HCl rings showed extended release. The results indicate
that the matrix structure of the implant and contact lens restricted the
release of the moxifloxacin HCl. It was also observed that as we in-
creased the amount of the moxifloxacin HCl loading in the implants, the
release duration was improved. The HPLC spectra of the moxifloxacin
HCl released from the implant contact lenses did not show any de-
gradation peaks, which confirmed the chemical integrity of the moxi-
floxacin HCl.
The HA loading in the implant was uniform in all the three batches.
The in vitro release profile of the HA from the implant contact lenses
showed significant reduction (p < 0.01) in the burst release and the
release rate duration (sustained effect) was improved in comparison to
the soaked contact lenses. The sustained release of HA from the HA-
implant was due to the high molecular weight and chain like structure
of the HA, which resist it to cross the mesh structure of the HA-implant.
The mechanism of the HA release from the implant could be highly
complex involving relaxation of HA chain in implant matrix followed
by dissolution and release in the media.
3.3.3. In vitro release of moxifloxacin HCl from the implant contact lenses
after radiation sterilization
The in vitro release was also carried out after the dry sterilization
(radiation), as the major part of the moxifloxacin HCl was leached lost
during the monomer extraction and the wet sterilization (autoclave)
steps. We have performed in vitro flux study of moxifloxacin HCl im-
plant to evaluate the rate controlling factors (resistance barrier, either
implant matrix or lens matrix) which may be responsible for restricting
the release of moxifloxacin HCl from the implant contact lenses. We
have reported in our previous studies (Maulvi et al., 2017), that the
sterilization did not cause major loss of the HA and the factors con-
trolling the release of HA from the HA-implant were long chain polymer
structure of HA, matrix of implant and contact lens. Thus we have not
conducted in vitro studies of the HA implants and the implanted contact
lenses (after radiation sterilization). The cumulative release (µg) and
the release rate (ng/h) profiles of the moxifloxacin HCl from the im-
plants and implanted contact lenses (radiation sterilization) are pre-
sented in Figs. 9 and 10 respectively.
The in vitro release profiles of the radiation sterilized implant con-
tact lenses showed the cumulative moxifloxacin HCl release of
50.99 ± 10.25 µg, 97.57 ± 6.30 µg and 143.41 ± 9.02 µg from
MOX-HA-I-50-CL, MOX-HA-I-100-CL and MOX-HA-I-150-CL batches
respectively. The data showed the significant improvement in the cu-
mulative release and the release rate profiles of the implant lenses in
comparison to the wet sterilized lenses. The release rate at 12 h from
the wet sterilized contact lenses were in the range of 54 to 145 ng/h,
while the radiation sterilized contact lenses showed significant increase
in the values from 556 to 1375 ng/h. After 48 h, the wet sterilized
contact lenses showed release rate of 8.9–15.88 ng/h, while the radia-
tion sterilized contact lenses showed 43–191 ng/h. Also, after 96 h, the
MOX-I-150-CL batch showed release rate of 10 ng/h. The results clearly
suggest the advantage of the packaging and dispensing the implant
contact lenses in dry state using radiation sterilization rather than the
F.A. Maulvi et al. International Journal of Pharmaceutics 548 (2018) 139–150

Fig. 14. Images of the rabbit eyes (Group 1) Uninfected and untreated, (Group 2) Conjunctivitis was induced and treated with saline solution (Negative control),
(Group 3) Conjunctivitis was induced and treated with commercial eye drop solution containing (0.5% w/v) Moxifloxacin HCl (Positive control), (Group 4)
Conjunctivitis was induced and treated with the implant contact lenses (Test group). The conjunctivitis was developed (using staphylococcus aureus) on day 2 and the
treatment was started on day 3.

wet sterilization method. The release rate profiles were improved with results suggest the significant role of the contact lens matrix along with
increase in the loading of the moxifloxacin HCl in the implants. the implant matrix, as a barrier in extending the release rate of water
The in vitro release profile of the implant (i.e. without implantation) soluble moxifloxacin HCl. The mechanism of the extended drug de-
showed 78–90% release of the moxifloxacin HCl within 48 h. The livery, may involve diffusion of the STF in aqueous channels of the

148
F.A. Maulvi et al.
contact lens matrix, with subsequent penetration of STF in the implant,
followed by dissolution and diffusion of the moxifloxacin HCl in the
release media.
3.4. In-vivo drug release study
The in vivo drug release study (Fig. 11) was performed to compare
the tear concentrations of the moxifloxacin HCl achieved by the con-
tinuous use of the implant contact lenses (MOX-I-150,
148.06 ± 12.30 µg loading) with the conventional therapy of 0.5% w/
v moxifloxacin HCl (MOXIZEE) eye drop (one drop = 250 µg of moxi-
floxacin HCl). The implant contact lenses were used after hydrating at
the room temperature for 24 h using 2 ml of sterile STF, whereby
7.51 µg of moxifloxacin HCl was leached in the STF. The LOD (limit of
detection) of the moxifloxacin HCl was 10 ng. The pure moxifloxacin
HCl standard (95% w/w purity) and the drug released from the implant
contact lenses (24 h reading) showed the substantially similar high re-
solution mass spectra (Fig. 12). Thus, the LC–MS results confirmed the
integrity of the drug eluted from the implant contact lenses as moxi-
floxacin HCl.
The maximum concentration (Cmax) of 1378.16 ± 643.64 µg/ml
was measured in the rabbit tear fluid at 5 min in the eye drop group,
followed by the rapid decline. The tear kinetic profile was found to be
consistent with the reported studies that too demonstrated rapid decline
in the concentrations within 2 h (Westermeyer et al., 2011; Stroman
et al., 2005; Callegan et al., 2003; Miller, 2008). While the implant
contact lenses showed an initial burst release (Cmax)
560.22 ± 416.89 µg/ml followed by extended release in the tear fluid
up to 48 h. The concentration of the moxifloxacin HCl in tear fluid re-
mained above the MIC (4 µg/ml) for Staphylococcus aureus, the most
frequent cause of the conjunctivitis in humans. Prolonged retention of
the moxifloxacin HCl in the pre-corneal area using the implant contact
lenses can substantially decrease the dose and dosing frequency of the
moxifloxacin HCl to achieve the desired therapeutic levels in compar-
ison to the eye drop therapy.
3.5. Efficacy study
The conjunctivitis was successfully induced in the rabbit eyes after
48 h using the young culture of the Staphylococcus aureus, as confirmed
by the symptoms of conjunctival edema of the eyelids, beefy red con-
junctiva and the swollen eye lids. No significant difference (p > 0.01)
in the conjunctival scores were observed among the group 2, 3 and 4
(Figs. 13 and 14). On day 3, the treatment with eye drop and the
contact lens was started in the group 3 and 4 respectively. After 24 h of
treatment, i.e. on the 4th day, the discharge was reduced in the group 4,
while no improvement was observed in the group 2 (saline treated) and
the group 3 (eye drop treatment). On the 5th day, the inflammatory
symptoms in the group 3 and 4 was significantly reduced (p < 0.01) in
comparison to the group 2 (Negative control). On the third day of the
treatment, i.e. 6th day, the rabbits’ eye in the group 3 and 4 showed no
discharge along with the minimal congestion and edema. The eyes were
completely cured on the 4th day of the treatment in the group 3 and 4.
While the inflammatory symptom still persisted in the group 2. The
outcome of the study suggests that, a single low dose (148 µg of mox-
ifloxacin HCl) implant contact lens was as effective as the frequent high
dose eye drop therapy.
4. Conclusion
The study demonstrated the successful application of the im-
plantation technology for the dual delivery of the moxifloxacin HCl and
HA to treat the bacterial conjunctivitis without altering the critical lens
properties. The AFM report confirmed the smooth surface of the im-
plant contact lenses for the comfort wear. The implant contact lenses
showed the major loss (leaching) of moxifloxacin HCl during the
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International Journal of Pharmaceutics 548 (2018) 139–150
monomer extraction and the sterilization step, which was resolved by
sterilizing the lenses in the dry state using radiation sterilization tech-
nique. The in vivo drug release study showed sustained moxifloxacin
HCl release for more than 48 h in the tear fluid, suggesting the im-
provement in the drug residence time using the implant contact lenses.
The in vivo efficacy study in the conjunctivitis induced rabbits’ eye
showed equivalent healing effect with the single implant contact lens in
comparison to the frequent high dose eye drop therapy. From this re-
search work, it was concluded that the concept of the semi-circular
rings implanted contact lenses have a strong potential to serve as a good
platform for the sustained ophthalmic drugs delivery to treat the con-
junctivitis.
Disclosures
There are no potential conflicts of interest to disclose for this work.
Acknowledgments
This research project was funded by Uka Tarsadia University, under
Research Promotion Scheme (UTU/RPS/2693/2017).
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