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Journal of Drug Delivery Science and Technology 41 (2017) 144e156

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Journal of Drug Delivery Science and Technology


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

TPGS stabilized sublingual films of frovatriptan for the management of


menstrual migraine: Formulation, design and antioxidant activity
Harmanpreet Singh a, b, Jasjeet Kaur Narang c, *, Yash Paul Singla d,
Ramandeep Singh Narang e, Vijay Mishra b
a
I.K.G Punjab Technical University, Kapurthala, Punjab, India
b
Department of Pharmaceutics, Lovely Institute of Technology (Pharmacy), Lovely Professional University, Phagwara, Punjab 144411, India
c
Department of Pharmaceutics, Khalsa College of Pharmacy, Amritsar, Punjab, India
d
Guru Jambheshwar University of Science & Technology, Hisar, Haryana, India
e
Department of Oral and Maxillofacial Pathology, Shri Guru Ram Das Institute of Dental Sciences and Research, Amritsar, Punjab, India

a r t i c l e i n f o a b s t r a c t

Article history: This work has been carried out to formulate and optimize mucoadhesive sublingual films of Frovatriptan
Received 26 February 2017 succinate monohydrate (FSM) using hydroxyethylcellulose (HEC) by solvent casting method. Frovatriptan
Received in revised form has low bioavailability (~27%) due to high first pass metabolism and lowest efficacy in 2 h pain free
21 May 2017
response among other triptans due to slow onset of action. Sublingual administration will improve the
Accepted 9 July 2017
bioavailability of FSM by providing direct access to systemic circulation bypassing high first-pass effect
Available online 11 July 2017
with rapid absorption and instant onset of action. Prepared sublingual films were then evaluated for
weight variation, thickness, surface pH, content uniformity, mechanical and mucoadhesive properties,
Keywords:
Frovatriptan succinate monohydrate
swelling index, in vitro drug release and permeation studies. Various permeation enhancers were also
Sublingual tried to improve the permeation of drug through sublingual mucosa. Among different permeation en-
Mucoadhesive hancers, Polysorbate 80 at 2% v/v in film showed highest permeation of drug (around 100% at 2 h) with
Permeation enhancers highest Jss and Kp of 223.77 mg/cm2 hr and 0.179 cm/h respectively through sublingual mucosa. Finally,
Antioxidant TPGS (D-a-tocopherol polyethylene glycol succinate 1000) was loaded in Polysorbate 80 (2% v/v) films to
further enhance drug permeability and provide antioxidant properties.
© 2017 Elsevier B.V. All rights reserved.

1. Introduction Sublingual administration offers a convenient route for systemic


availability of drug showing advantage of direct entry into systemic
Among women, migraine stands fifth influential cause of med- circulation bypassing hepatic first pass effect [6]. In addition, low
ical abnormality where as it is one of the top twenty causes of enzymatic activity, high blood supply and the thin non-keratinized
medical abnormality in men [1]. Migraine has painstaking and sublingual mucosa allows exceptionally good drug absorption to
disabling health status among its patients. It depicts repetitive, obtain high plasma drug concentration, which leads to quick
unilateral and throbbing attacks of headache varying from medium response against migraine. However, some potential problems
to high intensity [2]. The symptoms of migraine may vary among associated with sublingual administration are saliva wash-out ef-
individuals but usually include nausea, photophobia and phono- fect, involuntary swallowing and difficulty of keeping dosage form
phobia [3]. The symptoms may worsen gradually. Migraine pain in contact [7]. To ensure a prolonged retention of the dosage form
achieved a peak after 2e12 h followed by gradual mitigation. with the sublingual mucosa surface and to overcome the removal
However, the duration may vary from 4 to 72 h [4]. Thus the drugs by the flushing action of saliva, the sublingual formulations need to
with a quick onset of pharmacological effect are often preferred so possess mucoadhesive properties. In this context, various
as to resume the functional abilities of patient as soon as possible mucoadhesive polymers have been used in sublingual formulations
[5]. to impart mucoadhesion; some of which include chitosan, carbo-
pol, cellulose derivatives etc [8]. Frovatriptan, a second-generation
triptan is generally prescribed to the migraine patients, is a 5-
* Corresponding author. hydroxy triptamine (5-HT) receptor agonist with highest affinity
E-mail address: jasjeet2975@yahoo.com (J.K. Narang). to 5-HTB and 5-HTD receptors acting on extracerebral and

http://dx.doi.org/10.1016/j.jddst.2017.07.008
1773-2247/© 2017 Elsevier B.V. All rights reserved.
H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156 145

intracranial arteries and restrains excessive dilation of these vessels analytical grade and procured from Merck (Mumbai, India) and
in the patients of migraine, which makes it an appropriate partic- Loba Chemie (Mumbai, India).
ipant to be tried through.
In spite of the fact that frovatriptan has highest agonist activity 2.2. Formulation of placebo films
for 5-HT1B receptor and third highest activity for 5- HT1D receptors
with low reoccurrence rate of migraine among all the triptans, its The HEC is famous for good mucoadhesive film forming ability.
application is limited due to poor bioavailability (24% in males and It dissolves readily in water and the pH of resulting solutions is
30% in females) associated with first pass metabolism after oral around 7, which is close to the physiological salivary pH (5.8e7.4)
administration [9]. Besides this, the peak response of frovatriptan is [13]. In preparation of films, HEC with or without propylene glycol
achieved after 4 h of administration of available marketed tablet (plasticizer) at various concentrations was used. The sublingual
dosage forms, which is not desirable for the treatment of migraine films were made by solvent casting technique using 25 ml of
because as per International Headache Society (IHS) guidelines, a distilled water. The developed films were then examined for sur-
treatment is considered good for migraine if pain free response is face excellence, smoothness, ease of removal from petri plate and
achieved in 2 h after drug administration [10e12]. Therefore, in mechanical properties.
order to surmount the drawbacks accompanied with oral dosage
form of drug, an attempt was made to develop a sublingual dosage 2.3. Preparation of drug loaded films
form of frovatriptan with rapid onset of action. Further physi-
ochemical properties of drug, like low molecular weight The sublingual films of FSM were prepared by the conventional
(379.41 Da) and the low dose (2.5 mg) make it a suitable candidate solvent casting method [13,22]. HEC was dissolved in prewarmed
for administration through sublingual route. double distilled water maintained at 40  C while stirring which was
In this study, mucoadhesive sublingual films of frovatriptan continued for further 45e50 min to produce a clear solution. Then
succinate monohydrate (FSM) were developed and optimized. mannitol, drug with or without penetration enhancers (Chitosan,
Hydroxyethylcellulose (HEC), a nonionic water-soluble polymer has Transcutol®HP and Polysorbate 80) were added and stirred further
been used to prepare these sublingual mucoadhesive films [13,14]. for 2 h. Chitosan which has been used in the preparation of films
Different permeation enhancers such as chitosan, transcutol®HP was dissolved in glacial acetic acid (0.1 M) at 1% w/v concentration
and polysorbate 80 have also been tried to ameliorate the perme- and the resulting solution was evaporated to dryness. The dry
ation of drug via sublingual mucosa. Finally, in the best film batch residue of chitosan obtained was then redissolved in double
showing highest drug permeability, D-a-tocopherol polyethylene distilled water before adding HEC and other ingredients during the
glycol succinate 1000 (TPGS; 0.1 mg/ml) has been loaded for further preparation of films [23e25]. Wherever TPGS was added, drug and
improvement in drug permeability through the sublingual mucosa TPGS solution was prepared in 5 ml of distilled water which was
[15,16]. Thus the overall objective was to prepare and examine TPGS then added in HEC solution followed by addition of mannitol and
stabilized FSM sublingual films with the purpose to enhance ther- penetration enhancer. Then lastly 0.1 ml of propylene glycol (PG)
apeutic efficacy and bioavailability of FSM for improving the overall was added dropwise in solution while stirring which was then
management of migraine. again stirred for 45 min. The resulting solution was sonicated at
The idea of using TPGS is also based on the fact that it is non- least 60 min for the removal of any air bubbles entrapped. The
ionic water soluble derivative of Vitamin E. Vitamin E is effective solution was then cast on the Teflon coated glass petriplate of 6 cm
in relieving symptoms associated with menstrual migraine [17]. diameter which was then kept in hot air oven maintained at 40  C
The probable reason behind this phenomenon is that one of the for overnight with an inverted funnel over it to prevent sudden
events responsible for pathogenesis of migraine is oxidative stress evaporation. After drying, the films were observed for possible
due to generation of intracellular reactive oxygen species (ROS) imperfections and entrapped air after their careful removal from
which are free radicals implicated in pain etiology. Oxidative stress the petriplate. The images of the prepared films are shown in Fig. 1.
plays an important function in the migraine by controlling cerebral The prepared film was then cut according to the size required for
flow of blood and energy metabolism, each of the two may result in testing (3 cm length and 1 cm width). The cut samples were then
activating the beginning of attacks of migraine [18e20]. The anti- covered with parafilm and stored in a desiccator. The compositions
oxidant nature of TPGS which was used in formulation of sublin- of various sublingual films are shown in Table 1.
gual films would assist in lowering the levels of free radicals and
thus play an important function of this current work related to 2.4. Characterization and evaluation
management of migraine [21].
2.4.1. Weight uniformity, thickness and surface pH
2. Materials and methods Assessment regarding weight and thickness variation from the
film of each batch was performed on 5 films. Films of different
2.1. Materials batches were directly weighed on analytical balance to assess
weight uniformity and thickness was measured in five assorted
Frovatriptan succinate monohydrate (FSM), Transcutol®HP and locations (centre and 4 corners) of the film with the help of
Hydroxyethylcellulose (0.1 K) were obtained from Azakem Chem- micrometer (Outside micrometer, India) [26]. The surface pH of
icals (Hyderabad, India), Gattefose (Saint-Priest, Cedex, France) and each film (3 cm length and 1 cm width) was examined using pH
Continental chemicals (Delhi, India), respectively. TPGS (D-a- meter (LT-11 model, Auto digital pH meter, Labtronics, India). At
Tocopherol PEG 1000 succinate) was obtained from Sigma Aldrich normal room temperature, 1 ml of distilled water was poured on
Company, France. Chitosan with degree of deacetylation 90% was the film. After 60 s, the pH was measured by pH meter after letting
obtained from HiMedia (Mumbai India). Polysorbate 80 and Tri- it to equilibrate for 60 s with the film surface. The pH test was
chloroacetic acid were obtained from Thermofisher scientific, carried out on three films of each batch [27].
Mumbai, India. Potassium ferricyanide was obtained from Avantor
Performance Materials (Ankleswar, India). Acetonitrile and meth- 2.4.2. Morphology study by SEM
anol of HPLC grade were purchased from High Purity Laboratory The surface morphology of pure drug and distribution of drug in
Chemicals, Mumbai. All other chemicals and reagents used were of drug loaded film were investigated using scanning electron
146 H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156

Fig. 1. Images of the HEC film (A) Plain and (B) Drug loaded.

Table 1
Composition of the different prepared sublingual films.

Ingredients Formulation batches

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11

FSM (mg) 36.86 36.86 36.86 36.86 36.86 36.86 36.86 36.86 36.86 36.86 36.86
HEC (mg) 375 500 375 375 375 375 375 375 375 375 375
PG (ml) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
MNT (mg) e e 62.5 125 187.5 125 125 125 125 125 125
CHT (% w/w) e e e e e 1 2 e e e e
TC (% v/v) e e e e e e e 2 4 e e
P-80 (% v/v) e e e e e e e e e 1 2
Water (ml) 25 25 25 25 25 25 25 25 25 25 25

FSM ¼ Frovatriptan succinate monohydrate, HEC ¼ Hydroxyethylcellulose, PG ¼ Propylene glycol, MNT ¼ Mannitol, CHT ¼ Chitosan, TC ¼ Transcutol® HP, P-80 ¼ Polysorbate
80.

microscope (JSM 6100 JEOL, Tokyo, Japan). Samples of pure drug original area of the film. Finally, modulus of elasticity (EM) of films
and drug loaded film of appropriate size were mounted separately was calculated from the below mentioned equation [30e32].
onto metal stub by double-sided adhesive tape. The stubs were
then vacuum coated with gold by using fine coat ion sputter (JFC- EM ¼ TS=½Ls  Lo=Lo
1100 JEOL, Tokyo, Japan) before analysis. Finally, SEM images were Ls ¼ Film length after elongation
obtained at magnification of 800 using JSM-6100 scanning mi- Lo ¼ Original film length
croscope at an accelerating voltage of 15 KV [28].

2.4.3. Drug content uniformity 2.4.5. Mucoadhesion strength


The content uniformity of the films was determined by cutting 3 Mucoadhesion strength testing was carried out using the
small films representing 3 distinct locations (centre & 2 corners) mucoadhesive test apparatus prepared by modifying double beam
within a film of each batch. Drug was then extracted from each film physical balance as per method described in Shidhaye et al. 2008
in a beaker containing 100 ml of pH 6.8 simulated saliva by stirring [33]. The porcine sublingual mucosa used for the test was sourced
over magnetic stirrer for 3 h. After filtration and suitable dilution from a nearby butcher and used within 2 h after slaughtering of the
absorbance was determined at 244 nm with the help of UV spec- pig. It was washed with pH 6.8 simulated salivary fluid before using
trophotometer. For each prepared formula of batch, a placebo film it for mucoadhesion studies. The mucoadhesive strength of the film
was also prepared which served as a blank during UV analysis. The was calculated in terms of minimum weight in gram required to
content of drug in each batch was depicted as mean ± standard rupture the bioadhesive bond between the film and mucosa. The
deviation [29]. test was conducted in triplicate for each batch.

2.4.4. Mechanical properties 2.4.6. Ex vivo mucoadhesive time


Mechanical properties of the films with 3 cm length and 1 cm of Ex vivo mucoadhesive time has been determined after applying
width were evaluated by employing texture analyzer (TAXT plus, the sublingual film on newly excised porcine sublingual mucosa.
Stable Micro systems Ltd, Godalming, UK). This test was conducted The sublingual mucosa was used within 2 h after pig sacrifice by
by using probe A/TG; Tensile GRIPS, with trigger force of 3 g and fixing in the inner surface of the beaker using Fevi kwik. The sub-
testing speed of 0.05 cm/s. The extensibility (mm) and the force (N) lingual film was then damped with 50 ml of pH 6.8 simulated sali-
required to rupture the films was measured. Measurements were vary fluid and stuck to the porcine sublingual mucosa by employing
taken for three films of each batch. Tensile strength (TS) was then a light push with a finger tip for 20 s. Then 200 ml of pH 6.8
obtained by dividing force (N) required to rupture the film by the simulated salivary fluid kept at 37  C was added in the beaker in
H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156 147

such a way that sublingual mucosa containing film was fully dip- mounting in Franz diffusion cell to ensure removal of the soluble
ped. After 2 min, the beaker was stirred at 150 rpm to replicate the components present in it. After mounting the mucosa in Franz
buccal cavity surrounding. During the test, the time taken by the diffusion cell with mucosal surface facing upward, membrane sta-
film to fully erode or separate from the mucosa was carefully bilization was carried out for 4e5 h. After stabilization of mucosa,
viewed as the ex vivo mucoadhesion time. The study was per- sublingual films were kept in the donor chamber with 2 ml of pH
formed in triplicate for each batch [33,34]. 6.8 simulated saliva. At the fixed intervals of time i.e. 2, 5, 10, 20, 30,
40, 60, 90 and 120 min, 3 ml of sample was removed from the re-
2.4.7. Swelling studies ceptor chamber and replaced with an equal volume of fresh pH 7.4
Swelling tests were executed in pH 6.8 simulated saliva buffer by phosphate buffer kept at 37 ± 0.5  C. The withdrawn samples were
noting down the increase in the weight of the film at the various then assayed for FSM by UVeVisible spectrophotometer at 244 nm
intervals of time. The films of the given batch were placed sepa- after filtration and appropriate dilution [43,44]. The total amount of
rately in individual baskets made of stainless steel mesh and frovatriptan permeated per unit area was then estimated for the
weighed (W1) and then immersed in beaker containing pH 6.8 three measurements of the given batch and plotted versus time.
simulated saliva kept at 37  C. After fixed intervals of time i.e. 5, 10, From these curves different permeation parameters i.e. steady state
15, 20, 25, 30, 45, 60, 90 and 120 min respectively, the baskets flux (Jss), which is the slope of the linear section of the curve,
containing films were separated from the buffer and excess buffer permeability coefficient (Kp ¼ Jss/Cv), where Cv is the total drug
over the mesh surface was gently removed with the help of filter concentration in the donor compartment and permeation
paper. The baskets containing the films were then weighed (W2) enhancement ratio (PER¼ Kp of FSM film with permeation
and then placed back into the buffer. The increase in weight of the enhancer/Kp of FSM without permeation enhancer) were calcu-
film at various time intervals was noted down and swelling index lated [45].
was then calculated using the following equation:
2.8. Evaluation of excipient-drug interactions
SI ð%Þ ¼ ½ðW2  W1Þ  100=W1
The excipientedrug interactions were examined with the help
where W1 was the initial weight of film at t ¼ 0 and W2 was the of FTIR spectrophotometer (Thermo Nicolet, Thermo Scientific,
weight of hydrated films at time t. The experiment was then carried USA) at the frequency range of 500e4000 cm1 with a resolution of
out for three films of a given batch [35,36]. 2 cm1. The FTIR spectra of optimized film containing drug and
pure drug were recorded using an FTIR spectrophotometer by KBr
2.5. In vitro drug release studies pellet method and characteristic peaks obtained from them were
then compared.
In vitro drug released studies were performed in 250 ml of pH
6.8 simulated saliva maintained at 37 ± 0.5  C in USP Type II (paddle 2.9. Antioxidant activity by reducing power assay
type) dissolution apparatus (LABINDIA DS 8000, LabIndia Analyt-
ical Instrument Pvt Ltd, Mumbai) at 50 rpm. For the study film The anti-oxidant potential of the TPGS loaded optimized film,
(3 cm  1 cm) containing 2.5 mg of frovatriptan was used. Five ml of FSM suspension and optimized film without TPGS was analogized
samples were withdrawn at the time intervals of 1, 2, 5, 10, 15, 20, with standard anti-oxidant i.e. ascorbic acid using already estab-
25 and 30 min followed by replacement with fresh media kept at lished method of reducing power assay [46]. In this method
37 ± 0.5  C. These withdrawn samples were then passed through different working solutions namely ascorbic acid in distilled water,
0.45 mm nylon filter, diluted suitably and analyzed spectrophoto- optimized film containing TPGS in distilled water, pure drug in
metrically (UV-1800, Shimadzu Corporation, Kyoto, Japan) at distilled water and optimized film without TPGS in distilled water
244 nm. In vitro dissolution studies were carried out on 3 films for were prepared in different concentrations i.e. 5, 10, 20, 40, 80 and
each batch and the mean value (±SD) was reported [37]. Various 100 mg ml1. Then 1 ml of different working solutions were then
in vitro drug release models like zero order, first order, Higuchi, blended with 2.5 ml each of two solutions i.e. 0.2 M phosphate
Peppa and Hixson Crowell were fitted to in vitro drug release of buffer (pH 6.6) and 10% of potassium ferricyanide. The prepared
optimized film formulations so as to find out the drug release mixtures were then incubated for 20 min at 50  C and finally 10%
mechanism. trichloroacetic acid (2.5 ml) was added. This final mixture was
again centrifuged at 3000 rpm for 10 min. The top most layer of the
2.6. Loading of TPGS in film solution (2.5 ml) was separated which was further mixed with
2.5 ml of distilled water and 0.5 ml of 0.1% ferric chloride. The
D-a-tocopherol polyethylene glycol succinate 1000 (TPGS) was absorbance of the prepared solutions was then measured at 700 nm
loaded in the HEC films for permeation enhancement and antiox- by UV spectrophotometer.
idant properties in the concentrations of 0.05, 0.1 and 0.15 mg/ml
[15,21]. TPGS loaded films were then evaluated for the permeability 2.10. Accelerated stability studies and shelf life
study and the best formulation batch showing highest permeability
was further evaluated for its antioxidant potential. The stability study for sublingual films of frovatriptan was car-
ried out as per ICH guidelines at 40 ± 2  C and 75 ± 5% RH [47]. The
2.7. Permeation studies optimized film formulations were placed in the stability chamber
for 3 months after first wrapping in a butter paper followed by
Porcine sublingual mucosa was selected as a model simulating wrapping in an aluminum package. The effect of storage for 3
human sublingual mucosa for carrying out the permeation studies months was investigated on the physiochemical characteristics of
as it is similar in composition, structure, and permeability mea- the sublingual films. The films were then evaluated for appearance,
surements to human oral mucosa [38e42]. Mucosa with thickness weight variation, FSM content, surface pH, mechanical properties,
of around 0.5 mm was excised by blunt dissection with the help of bioadhesive characteristics and permeability study [30]. The shelf
scalpel. The excised mucosa was then cut into appropriate sizes and life of the optimized films was determined after packaging it as
equilibrated in pH 6.8 simulated salivary fluid for 30 min before discussed above and then storing at different temperatures i.e. 30,
148 H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156

40, 50 and 60  C for 3 months. The films kept at different temper- 3. Results and discussion
ature conditions were withdrawn at 0, 1, 2, and 3 months and log
concentration of drug remaining at different time intervals was 3.1. Preparation of placebo films
calculated. The log concentration of drug remaining at various
temperatures was then plotted against time. From the slopes of Table 2 shows the influence of polymer concentration with and
lines at each temperature, the corresponding rate constant (K) was without plasticizer on the preparation of films. The results of the
obtained by using equation given below: initial studies revealed that films of H5 batch showed best results
overall. This formula of batch was then selected for formulation of
Slope ¼ K=2:303 drug loaded films.
Finally, Arrhenius plot was constructed by plotting the value of
log K at different temperature versus the reciprocal of absolute 3.2. Physicochemical characteristics of the drug loaded sublingual
temperature. Using this plot, K25 was obtained by extrapolation films
which was lastly used to calculate shelf life (t90) using equation
given below: The sublingual films of all batches had good flexibility, strength
and homogeneity as shown in Table 3. The average thickness of the
Shelf life ¼ 0:1052=K25 films of all the batches ranged from 0.218 ± 0.03 to 0.278 ± 0.02 mm
whereas the weight of the different formulation batches ranged
from 56.54 ± 1.62 to 93.48 ± 2.93 mg. The increase in thickness and
weight of film of F2 batch as compared to other batches might be
2.11. Histopathology studies due to the increased amount of HEC. The surface pH for the for-
mulations batches was found to be in range from 6.63 to 6.97. Since
In order to ascertain non toxic potential of the prepared films on this range is near to salivary pH (6.5e7.2), no mucosal irritation is
mucosa histopathological studies were conducted by placing the expected [48]. Drug content uniformity in the sublingual films was
film on porcine tissue obtained from floor of mouth for 2 h and evaluated and the values ranged from 98.03 ± 1.59% to 101.38 ± 3.10
comparing it with same tissue incubated in simulated saliva pH 6.8 for the different batches. The results of content uniformity
without any treatment. After fixing the tissue with 10% formalin it confirmed uniformity of drug content in the films. Observing the
was routinely processed and embedded in paraffin. The paraffin data of the uniformity of weight, thickness and surface pH it could
sections were cut on glass slides and stained with hematoxylin and be stated that the results obtained were quite satiated with regard
eosin. Finally, the stained samples were examined under light mi- to changes of these parameters between films of same batches.
croscope to detect any cellular infiltration and tissue damage [33].
3.3. SEM

2.12. Statistical analysis The surface morphology of the pure drug and drug loaded
sublingual film was characterized using SEM as shown in Fig. 2. The
All the results are depicted as mean ± standard deviation. Paired SEM image of pure drug (Fig. 2A) showed irregular shape crystals of
t-test was performed to compare the differences of means using the drug which were uniformly dispersed in SEM image of the drug
GraphPad InStat 3.0 where values at p < 0.05 were considered loaded film (Fig. 2B). Moreover, no fractures were observed in drug
significant. loaded film.

Table 2
Influence of polymer concentration with and without plasticizer on film preparation.

Batch HEC conc PG (ml) Observation

H1 1% w/v or 250 mg e Clear, Transparent and complete film but very brittle
H2 1% w/v or 250 mg 0.1 ml Brittleness decreased but the film was not able to sustain its integrity after some time
H3 1% w/v or 250 mg 0.2 ml Brittleness further decreased but the film was not able to sustain its integrity after some time
H4 1.5% w/v or 375 mg e Clear, Transparent and complete film which was less brittle
H5 1.5% w/v or 375 mg 0.1 ml Clear, Transparent and complete film which was not brittle

Table 3
Physicochemical characterization of various film formulations.

Batches Thickness* Weight* Surface Content Tensile Extensi-bility* Elastic modulus* (N/ Muco- Ex vivo muco-adhesive time*
(mm) (mg) pH* uniformity strength* (mm) mm2) adhesive (hr)
per patch* (mg) (N/mm2) strength* (g)

F1 0.226 ± 0.01 56.54 ± 1.62 6.86 ± 0.23 99.06 ± 2.04 5.93 ± 0.25 14.98 ± 0.60 5.95 ± 0.45 17.45 ± 0.45 4.58 ± 0.23
F2 0.278 ± 0.02 93.48 ± 2.93 6.92 ± 0.30 98.74 ± 1.99 6.28 ± 0.32 11.80 ± 0.55 8.01 ± 0.77 20.10 ± 0.97 5.77 ± 0.45
F3 0.228 ± 0.01 63.23 ± 2.54 6.75 ± 0.62 98.99 ± 2.01 5.76 ± 0.21 16.60 ± 0.34 5.21 ± 0.29 16.91 ± 0.32 3.65 ± 0.21
F4 0.224 ± 0.02 70.23 ± 2.68 6.73 ± 0.37 98.73 ± 2.49 5.00 ± 0.27 17.56 ± 0.58 4.27 ± 0.18 16.23 ± 0.15 2.84 ± 0.36
F5 0.234 ± 0.01 78.42 ± 1.78 6.67 ± 0.34 98.03 ± 1.59 4.59 ± 0.32 18.48 ± 0.60 3.73 ± 0.30 15.82 ± 0.21 2.14 ± 0.10
F6 0.224 ± 0.02 80.16 ± 2.19 6.90 ± 0.26 101.38 ± 3.10 5.27 ± 0.17 18.13 ± 0.73 4.36 ± 0.25 18.82 ± 0.57 4.67 ± 0.38
F7 0.224 ± 0.01 80.96 ± 2.03 6.98 ± 0.23 99.48 ± 3.12 5.47 ± 0.27 18.55 ± 0.50 4.43 ± 0.32 20.04 ± 0.62 6.10 ± 0.47
F8 0.232 ± 0.02 76.41 ± 1.82 6.97 ± 0.18 99.94 ± 2.30 4.91 ± 0.17 18.16 ± 0.70 4.06 ± 0.24 15.95 ± 0.72 2.98 ± 0.45
F9 0.234 ± 0.03 82.88 ± 2.52 6.63 ± 0.28 100.02 ± 2.82 4.78 ± 0.25 18.99 ± 0.43 3.77 ± 0.11 16.39 ± 0.48 3.03 ± 0.49
F10 0.238 ± 0.03 71.91 ± 2.22 6.65 ± 0.20 99.53 ± 3.11 4.52 ± 0.20 19.68 ± 0.44 3.44 ± 0.11 16.61 ± 0.42 2.65 ± 0.38
F11 0.218 ± 0.03 75.94 ± 2.39 6.77 ± 0.35 99.74 ± 2.61 4.00 ± 0.22 20.57 ± 0.68 2.93 ± 0.28 16.85 ± 0.77 2.76 ± 0.51

*All above values represent the mean ± standard deviation and n ¼ 5 for weight and thickness and n ¼ 3 for others.
H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156 149

Fig. 2. SEM images of (A) Pure drug and (B) Drug loaded film.

3.4. Mechanical properties 3.6. Swelling studies

Texture analyzer was used to estimate the mechanical prop- Fig. 3 demonstrate the swelling profiles of the formulations F-1
erties of prepared films. Tensile strength and elastic modulus are to F-11 in pH 6.8 simulated saliva fluid. In vitro swelling studies
an index of mechanical strength of films. Extensibility indicates revealed that all films except that containing chitosan showed
flexibility of films i.e. the extent to which the film can be stretched highest swelling index % at 5 min whereas for the chitosan con-
by application of force. Results obtained as given in Table 3 taining films maximum increase in swelling occurred at 15 min.
showed that there was an increase in the tensile strength and Afterwards the weight of the film decreased markedly as the film
elastic modulus whereas decrease in the extensibility with an got dissolved consequently leading to a fall in the swelling index %.
increase in the polymer concentration in film (F2 batch). It was The addition of mannitol in the films leads to a decrease in the %
also found that increase in the concentration of mannitol in films water-absorption potential as compared to F1 films. However,
lead to a decrease the tensile strength and elastic modulus, with mannitol being a hydrophilic absorbing material should favor entry
an increase in the extensibility of films. The probable cause could of water in system [53]. This phenomenon could be explained
be that mannitol in higher concentration in the films softens the based on the fact that addition of mannitol makes the polymer soft
polymer thus decreasing its toughness [49]. The addition of chi- by getting itself dissolved, thus creating more pores and channels
tosan in the film did not have significant influence on the tensile through the polymer that in turn favoring the erosion of the
strength, elastic modulus and extensibility as compared to F4 films polymer. It was also found that the increase in the chitosan content
probably due to its low amount being added in the film. On the lead to a significant increase in the degree of swelling of the films
other hand, addition of Polysorbate 80 significantly lowered the and thus slowed down the erosion of the film. The results obtained
tensile strength and elastic modulus and increases the extensi- were comparable to the work done by the Shidhaye et al. 2008 [33].
bility of films, probably due to its plasticizer effect as reported in
literature [50].
3.7. In vitro dissolution studies

3.5. Mucoadhesion strength and ex vivo mucoadhesive time The in vitro drug release profiles of films of formulae F1 to F11
are shown in Fig. 4. On comparing F1 and F2 it was observed that
Based on the results as shown in Table 3, it was concluded that a there was a significant reduction (p < 0.05) in drug release of F2 as
higher concentration of HEC polymer (F2 batch) in the film increased compared to F1 and therefore F2 was discarded for further studies.
the mucoadhesive strength of films. The addition of mannitol in the The probable phenomena behind it may be that increasing the
films (F3eF5) lowered the mucoadhesive strength of the films with a polymer concentration in F2 lead to the formation of a water-
significant decrease in F5 film when compared to F1, probably swollen gel-like state which increased the diffusional pathway
because softening of polymer occurred on addition of mannitol [49]. and thus decreased the water uptake, which in turn lead to a
Also, a significant increase in the mucoadhesive strength of films was retarded the drug release. For batches F3, F4 and F5 mannitol was
found with the addition of chitosan (F6 batch) when compared to F4 added in concentrations of 0.25, 0.50 and 0.75% w/v respectively as
batch. Chitosan contains positively charged amino groups that it has a sweet taste, a good mouth feel, negative heat of solution,
interact with the negatively charged (at pH 6.8) sialic acid and sul- and dissolution enhancing properties [54,55]. Mannitol increased
phate residues of mucin resulting in mucoadhesion [51,52]. The the polymeric chain mobility by allowing greater water entry thus
addition of other permeation enhancers in batches F8  F11 did not leading to increased drug diffusion through the hydrated films.
seem to affect the mucoadhesive strength as compared to F4 batch. There was a significant increase (p < 0.05) in the drug release with
The mucoadhesion time of all films were found to be more than 2 h. films containing mannitol as compared to F1 films without
Moreover, a good correlation was found between mucoadhesive time mannitol. Among the film formulations (F1eF5), in the formulation
and mucoadhesive strength. The films which showed longest ex vivo batches F4 and F5 the amount of drug dissolved exceeded 80% in
mucoadhesion time were also found to show highest mucoadhesive 15 min which is the requirement of sublingual tablets [8,56]. Thus
strength. The results are comparable to the study done by Perioli et al. F4 batch which contained lower concentration of mannitol as
2004 [34]. The mucoadhesive time of various batches followed the compared F5 batch was selected and various permeation enhancers
order F7>F2>F6>F1>F3>F9>F8>F4>F11>F10>F5. like chitosan, Transcutol® HP and Polysorbate 80 were added
150 H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156

Fig. 3. Swelling behavior of film formulations (F1eF11) in simulated saliva (pH 6.8).

Fig. 4. In vitro dissolution profile of Frovatriptan sublingual films (F1eF11).


H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156 151

individually in different concentrations (F6eF11). Among the film to F4. Based on the results of dissolution and permeability studies,
formulations F6 and F7 containing chitosan, an increase in the F4 batch was selected in which various permeation enhancers were
concentration of chitosan had a significant negative effect on drug incorporated. For the formulation of sublingual dosage forms, the
release especially for the first 15 min. This could be explained by the drug candidate should have higher potency (dose < 10 mg), high
fact that chitosan forms a viscous gel layer at higher concentration lipophilicity (log P > 2), good water solubility, be presents in a
that acts as a barrier to the further penetration of the dissolution unionized form and should have a small molecular size (less than
medium making drug diffusion more difficult. For formulation F8 800 Da) [6]. Our drug candidate FSM is having higher potency
and F9 containing Transcutol® HP in different concentration, the (dose ¼ 2.5 mg), moderate lipophilicity (log P ¼ 1.2), hydrophilicity
increase in concentration of Transcutol® HP did not significantly (solubility>100 mg/ml), unionized form at sublingual pH (with pKa
affect dissolution of the drug. A very interesting phenomenon of 14.54) and low molecular size (379.41 Da) [8,59]. Our drug
occurred by the addition of Polysorbate 80 where lower concen- candidate FSM has all the required physiochemical properties
tration of it in F10 film (1% v/v) decreased the drug release whereas except lipophilicity, thereby requiring permeation enhancers to
higher concentration in F11 film (2% v/v) increased the drug release enhance the sublingual permeation [6]. Thus, different permeation
when compared to F4 films. enhancers like Chitosan [7], Transcutol® HP [60] and Polysorbate 80
The kinetic analysis of the in vitro release data of F11 formulation [60] were individually incorporated in the F4 batch to improve the
was done by fitting the results in various kinetic models (zero order, permeation of drug through sublingual mucosa. Chitosan when
first order, Hixson Crowell model, KorsmeyerePeppas model and used in concentration of 1% w/w in F6 batch was found to improve
Higuchi model). The results showed that Hixson and Crowell model the permeation of the drug but at higher concentration (2% w/w) in
was the best fit model to describe the kinetics of drug release with F7 batch exhibited less % drug permeation with lower steady state
highest correlation coefficient (r2) value of 0.983. According to this flux and permeation coefficient. The incorporation of Transcutol®
model, it is the drug particles dissolution rate that limits the drug HP and Polysorbate 80 individually in the formulation batches
release rate. The drug release rate is not limited by the diffusion (F8eF11) improved the permeation of the drug at all the concen-
that might occur through the polymeric matrix [57,58]. trations. Among all the permeation enhancers evaluated the F11
batch containing 2% v/v of Polysorbate 80 showed highest % drug
3.8. Permeability studies permeation (around 100% at 2 h) that was significantly higher
(p < 0.05) as compared to formulations containing other perme-
The results of drug permeability of the sublingual film across the ation enhancers. The formulation F11 had a Jss, Kp and PER of
porcine mucosa are shown in Fig. 5. The results of permeability 223.77 mg/cm2 hr, 0.179 cm/h and 173.79 respectively which were
study showed that the permeation of drug decreased significantly also significantly (p < 0.05) higher than Jss, Kp and PER of all the
(p < 0.05) with the increase in concentration of the polymer on formulations evaluated as shown in Table 4. The F4 batch film
comparing batch F1 with F2. This behavior can be correlated with without enhancer was assigned a value of 100 for PER. Based on the
in vitro drug release profiles from sublingual films that ultimately results, formulation F11 was chosen for incorporation of TPGS. The
influenced the availability of drug at the absorption site. Similarly, antioxidant nature of TPGS would provide a synergistic effect with
F4 batch showed significantly higher permeability than F3 batch. In frovatriptan for treatment and management of migraine by
F5 batch, a further higher concentration of mannitol did not seem reducing the levels of free radicals responsible for migraine pain.
to increase the permeability of the drug significantly as compared

Fig. 5. Comparison of permeation of Frovatriptan through porcine mucosa from various Frovatriptan sublingual films (F1eF11).
152 H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156

Table 4 the permeability of the drug as compared to F4 and F10 batches


Permeation parameters of Frovatriptan from films with and without permeation (Data not shown). Similar results were obtained when TPGS in
enhancers through porcine sublingual mucosa.
concentrations of 0.05, 0.1 and 0.15 mg/ml were individually loaded
Batches Permeation parameters in F11 batch to get batches HT1, HT2 & HT3 respectively. There was
Jss (mg/cm2 hr) Kp(cm/hr) PER a notable increase (p < 0.05) in drug permeability of HT2 batch
containing TPGS in concentration of 0.1 mg/ml as compared to HT1
F1 120.9 ± 7.59 0.097 ± 0.006 e
F2 113.47 ± 6.74 0.091 ± 0.005 e batch having TPGS in concentration of 0.05 mg/ml. Incorporation of
F3 118.17 ± 6.27 0.095 ± 0.005 e TPGS in further higher concentration (0.15 mg/ml) in HT3 batch
F4 128.5 ± 9.94 0.103 ± 0.008 100 caused a significant decrease in permeability of drug. The interplay
F5 133.93 ± 8.93 0.107 ± 0.007 e
of TPGS concentration dependent P-gp inhibition activity and
F6 147.13 ± 7.30 0.118 ± 0.006 114.56
F7 94.84 ± 4.39 0.076 ± 0.004 73.79 micelle formation might explain this phenomenon [15]. The entire
F8 145.13 ± 9.23 0.116 ± 0.007 112.62 results are shown in Fig. 6. Thus HT 2 batch was selected as opti-
F9 146.23 ± 6.24 0.117 ± 0.004 113.59 mized batch to carry out further studies.
F10 183.97 ± 12.67 0.147 ± 0.010 142.72
F11 223.77 ± 8.72 0.179 ± 0.007 173.79
3.10. Determination of excipient-drug interactions

The overlay FT-IR spectrum of drug (FSM) and optimized film of


3.9. TPGS loaded films frovatriptan are shown in Fig. 7. The FT-IR spectrum of FSM showed
typical peaks at 1410.34 cm1 C-N (stretch band), 3398.91 and
TPGS 1000 is a water soluble vitamin that consists of a lipophilic 3188.53 cm1 N-H (stretch band) owing to primary amide group,
head and hydrophilic PEG tail. The use of TPGS is already reported and 1478.97 cm1 C¼C (medium weak stretch band) owing to ar-
in cellulosic films [16,61,62]. It was incorporated in various con- omatic ring present. The FT- IR spectrum of the optimized film
centrations in HEC batches of F4, F10 and F11 with an idea to further showed same characteristic peaks corresponding to functional
increase the permeation of drug through sublingual mucosa and to groups as present in FTIR of pure drug. From the FT-IR spectra
provide antioxidant effect in brain. The enhanced permeation of the absence of any chemical interaction between the drug and excipi-
drug by TPGS 1000 in the interior of the cell is attributed to its ents in optimized drug film was concluded.
ability of inhibiting P-gp efflux transporters present on the plasma
membrane of cells of sublingual mucosa [63]. Frovatriptan being a 3.11. Reducing power assay
substrate for P-gp [59] could be effluxed out by these efflux
transporters which though being present in less amount in sub- The antioxidant activity of TPGS loaded film (HT 2) was
lingual mucosa than that of intestinal mucosa are important de- measured by using reducing power assay. In the reducing power
terminants of drug permeability [64]. TPGS in the concentration of assay, the antioxidant activity of the compound is assessed by
0.05 mg/ml and 0.1 mg/ml when loaded in F4 and F10 batches measuring the reducing capacity of the compound. Increased
improved the permeability of drug, which was however non- concentration of reducers (i.e. antioxidants) leads to increased
significant as compared to F4 & F10. Addition of TPGS at a con- reduction of the ferricyanide complex (Fe3þ) to the ferrous form.
centration of 0.15 mg/ml in F4 and F10 batches lead to decrease in The formation of Perl's Prussian blue was used to assess the

Fig. 6. Comparison of permeation of Frovatriptan through porcine mucosa from TPGS loaded films with F11 batch (without TPGS).
H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156 153

Fig. 7. FT-IR spectra of (A) Pure drug (B) Drug-loaded optimized film formulation (HT2).

Fe2þ.ions at 700 nm [65]. Higher absorbance of the test solution in vitro scavenging the reactive oxygen species [65]. FSM is also
implied more reducing power. The reducing power of the TPGS having indole and pyrrole ring in its structure which might have
loaded FSM film (HT2) in comparison with the FSM film formula- contributed to antioxidant effect. The TPGS loaded film formula-
tion (without TPGS), pure drug and ascorbic acid (standard anti- tions showed reducing power ability comparable with that of
oxidant) has been shown in Fig. 8. The data obtained highlighted an ascorbic acid. This might be due to presence of TPGS which has an
interesting outcome i.e. the reducing power of the pure drug (FSM) inherent antioxidant activity. The role of any other excipient in drug
increased with an increase in its concentration although it was loaded film except TPGS was also assessed for antioxidant activity
quite low as compared to ascorbic acid. The probable reason for the by determining the reductive power of different concentrations of
phenomena which we postulate is that the indole and pyrrole de- F11 film. Fig. 8 showed the reductive efficiency of F11 film as
rivative drugs have an inherent ability to show antioxidant effect by compared to the pure drug with no significant difference (p < 0.05)

Fig. 8. Comparison of antioxidant activity of Ascorbic acid, plain drug (FSM), HT2 and F11 formulation by reducing power assay.
154 H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156

Table 5
Evaluation of optimized FSM sublingual films (HT 2) during stability studies at 40  C/75% RH.

Time Appearance Weight (mg) Drug content (%) Surface pH Tensile strength Mucoadhesive strength (g)
(N/mm2)

0 Day Transparent, Smooth and non-sticky 75.77 ± 0.60 98.87 ± 2.43 6.84 ± 0.09 4.01 ± 0.25 17.58 ± 1.14
1 month Transparent, Smooth and non-sticky 75.75 ± 0.59 98.83 ± 2.44 6.80 ± 0.1 4.00 ± 0.24 17.56 ± 1.14
2 month Transparent, Smooth and non-sticky 75.74 ± 0.60 98.81 ± 2.43 6.76 ± 0.1 3.98 ± 0.24 17.54 ± 1.15
3 month Transparent, Smooth and non-sticky 75.73 ± 0.59 98.79 ± 2.44 6.72 ± 0.09 3.96 ± 0.24 17.53 ± 1.14

thus suggesting that the other excipients used in film had no Table 6
antioxidant activity of their own. The results indicated that HT2 Observation table for shelf life estimation.
film formulation loaded with TPGS had a remarkable potency to Absolute temperature (K) Slope K Log K 1/T  103
exhibit antioxidant activity by converting reactive free radicals into
298.0 e 0.0001 4.2594 3.355704
non-reactive ones thus breaking the free radical chain reaction. 303.0 0.000030 0.00006 4.2117 3.300330
Since, these reactive free radicals are responsible for pain associ- 313.0 0.000037 0.00008 4.0734 3.194488
ated with migraine, HT2 film formulation loaded with TPGS due to 323.0 0.000050 0.00012 3.9208 3.095975
its antioxidant property might alleviate it. 333.0 0.000070 0.00016 3.7926 3.003003

3.12. Accelerated stability studies and shelf-life


3.13. Histopathology studies

The stability study of optimized frovatriptan film packed in


The results of histopathology study revealed that microscopic
aluminum packs was carried out at 40 ± 2  C and 75 ± 5% RH for 3
structure of mucosa (Fig. 11) remained unaltered after application
months in a stability chamber. The results are summarized in
of the drug loaded film. No evidence of inflammation and cell ne-
Table 5. After 3 months the appearance, weight, drug content,
crosis was observed with the optimized film treated porcine mu-
tensile strength, mucoadhesive strength and surface pH of the films
cosa when compared to pH 6.8 simulated saliva incubated mucosa.
was found to be comparable with that of film samples at 0 day.
Thus, the developed HEC film formulation appeared to be safe for
There was also no significant change (p < 0.05) in the permeation
sublingual administration.
rate after storage for 3 months when compared to films at 0 day as
shown in Fig. 9. These findings suggest that frovatriptan films are
stable for 3 months. The shelf life of the optimized film formulation 4. Conclusion
was determined by calculating the log concentration of drug
remaining after storing them at 30, 40, 50 and 60  C for 3 months. FSM was successfully incorporated into mucoadhesive films
First-order kinetics was the order of degradation of frovatriptan in which could be delivered through the sublingual route. HEC was
film formulation as calculated from accelerated stability studies. used as a mucoadhesive polymer for sublingual delivery along with
The rate constant of reaction “K” at various temperatures was various penetration enhancers resulting in films with satisfactory
estimated from the slope of the plot between log concentration of physico-mechanical properties, good mucoadhesive strength, fast
drug remaining versus time as shown in Table 6. Then the Arrhe- drug release and maximum permeation without causing any
nius plot of the film formulation at various temperatures was damage to porcine sublingual mucosa. Finally, TPGS was loaded in
plotted between log K values at different temperatures versus the film to further improve the drug permeability and to provide
reciprocal of absolute temperature as shown in Fig. 10. Using the antioxidant effect. Antioxidant effect of TPGS will reduce the levels
plot, K25 was estimated. Finally shelf life of the film was calculated of free radicals which are implicated in migraine attack and would
using K25 which was found to be 1052 days. thus provide a synergistic effect with the drug in the management

Fig. 9. Permeation of Frovatriptan from the optimized film formulation across porcine mucosa after storage for 3 months at 40 C/75% RH.
H. Singh et al. / Journal of Drug Delivery Science and Technology 41 (2017) 144e156 155

Fig. 10. Arrhenius plot for the optimized film formulation.

Fig. 11. Histopathology of different sections of porcine sublingual mucosa [H&E stain; 100 magnification] (A) Incubated in simulated saliva (pH 6.8) for 2 h and (B) Treated with
optimized film for 2 h.

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