-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2669
FORMULATION AND EVALUATION OF ORAL THIN FILMS
CONTATING SAXAGLIPTIN
1D.Archana Jyothi
*,
2Ch.S.Vijaya Vani,
3Dr.V.Uma Maheshwar Rao
Department of Pharmaceutics, CMR College of Pharmacy,
Kandlakoya, Medchal Road,
Hyderabad-501401INDIA
Corresponding Author
D.Archana Jyothi
Department of Pharmaceutics
CMR College of Pharmacy, Kandlakoya, Medchal Road,
Hyderabad-501401, INDIA
Email: [email protected]
Mobile: +91 8125327241
International Journal of Innovative
Pharmaceutical Sciences and Research www.ijipsr.com
Abstract
The purpose of the present investigation was to formulate and
develop RDF of Saxagliptin for oral use
and deliver maximum amount of the drug in shortest duration of
time with most comfort to the patient.
Saxagliptin is an oral antidiabetic drug belongs to the class of
gliptins and is a dipeptidyl peptidase
enzyme inhibitor. Various grades of HPMC(E3 LV,E5 LV,E15 LV) as
film forming polymers, PEG 400
as plasticer, different flavours (lemon flavor ,passion fruit
flavour) Aspartame as sweetening agent,
Citric acid as saliva stimulating agent were used in the
formulation of rapidly dissolving films. FTIR
Studies show no incompatability among drug and excipients.15
different formulations were prepared by
using solvent casting method. The prepared formulations were
evaluated for taste, in-vitro
disintergration and dissolution. Other parameters measured for
evaluation of RDF include mechanical
properites % elongation and elastic modulus study. The optimized
batch E9 contanting HPMC (E3 LV),
PEG 400, Aspartame had acceptable characteristics in-vitro
disintergration time is 25 sec and in-vitro
dissolution drug realese in 2 min is 98% and taste masking
properties. ESEM study was also carried out to study the surface
morphology.
Keywords: Saxagliptin, HPMC, Flavours, PEG 400.
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2670
INTRODUCTION
Rapidly dissolving dosage forms (RDDF) have recently acquired
great importance due to their
properties such as quick disintegration and dissolution,
obviating need of water for disintegration
and especially suitable for pediatric and geriatric patients.
Orally disintegrating tablets (also called
quick disintegrating tablets, mouth dissolve tablets) are the
most common and widely used rapidly
dissolving dosage form [1]. Fast-dissolving drug delivery was
pioneered by scientists at Wyeth
Laboratories in the UK during the late 1970s, which resulted in
patenting of the “Zydis” drug
delivery system. Fast-dissolving drug delivery systems can be
manufactured by a variety of
technologies, including direct compression, wet granulation,
freeze drying, spray drying, vacuum
drying and use of super disintegrants [1]
Rapidly dissolving films (RDF)
Oral film strips have hit the mainstream in the last few years
as a new way of freshening the
breath. The wafers are slipped into the mouth and dissolve
quickly to release the mint flavour
(Pfister W,Ghosh T 2005).[2,3]. The product attributes that a
patient today seeks in a dosage form
are-
Better portability
Ease and accuracy of dosing
Overall convenience
These films generally dissolve within seconds to release the
active agents but can be modified to
release the drug more slowly depending upon film thickness and
selection of the polymer matrix.
A film or strip can be defined as a dosage form that employs a
water dissolving polymer which
allows the dosage form to quickly hydrate, adhere and dissolve
when placed on the tongue or in
the oral cavity to provide rapid local or systemic drug
delivery. Drug release may be either quick
or slow by varying the rate of dissolution of the films. The
breath freshening strip was created by
Pfizer‟s Warner-Lambert‟s consumer healthcare division, which
launched Listerine PocketPaks™
in 2001. Chloraseptic relief strips were the first oral thin
film product to incorporate a drug and
were introduced in the United States in September, 2003 by
Prestige Brands international for
relief of sore throat. Zengen Inc developed this new delivery
technology, which is a medicated
oral strip structured as a proprietary bilayer system. These
films typically contain water soluble
hydrocolloids such as HPMC, pullulan, pectin,
carboxymethylcellulose, an effective dose of
active agent, other additives such as flavoring agents,
plasticizers and preservatives. The
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2671
disintegration and dissolution characteristic of thin film is
dependent on thickness and
combination of hydrocolloids. RDF are already being used in
breath freshening product
introductions from Warner Lambert and Wrigley's in the USA and
Europe, and Boots in the UK,
as well as vitamin products. Consumers have now been exposed to
this concept through the
introduction of multiple breath-freshening products introduced
over the past 2 years, and the trend
is now towards developing over the counter (OTC) and
prescription products in this delivery
form. The delivery system is simply placed on a patient‟s tongue
or any oral mucosal tissue.
Instantly wet by saliva, the film rapidly hydrates and adheres
onto the site of application. It then
rapidly disintegrates and dissolves to release the medication
for oramucosal absorption or, with
formula modifications, will maintain the quick-dissolving aspect
but allow for gastrointestinal
absorption to be achieved when swallowed (Vollmer U,2006,
Corniello CM,2006). [4-12]
The benefits of film over conventional delivery systems are
numerous:
Faster absorption into the bloodstream;
More portable than syrups and tablets;
Easy to administer;
More cost-effective than conventional tablet solutions.
The key advantage for rapidly dissolving film is patient
compliance and convenience.
The main drawback is with drug loading. Drug loading is
generally limited to roughly 20mg. This
problem can be addressed by increasing the thickness of the
strip, but that in turn may change the
dosage form to slowly dissolving film. But drug companies have
been interested in this
technology as it provides fast, accurate dosing that is expected
to increase compliance,
particularly among children. There is no need for water or
measuring, and upon melting, the dose
of medicine is swallowed. The likely candidates for rapidly
dissolving films or oral thin films are
nicotine replacing its transdermal delivery, antiulcer drug and
antihistamine products. Prescription
products, antipsychotic and sleeping disorder drugs are the
potential candidates [4-12].
The Aim of the Present study was to formulate and develop RDF of
Saxagliptin for oral use and
deliver maximum amount of the drug in shortest duration of time
with most comfort to the
patient. Saxagliptin is an oral antidiabetic drug belongs to the
class of gliptins and is a dipeptidyl
peptidase enzyme inhibitor.
The RDF of Saxagliptin using various grades of HPMC E LV were
prepared by solvent casting
method
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2672
MATERIALS AND METHOD
Materials used
Saxagliptin, HPMC E3 LV,HPMC E5 LV, HPMC E15 LV, Sucralose,
Citric acid anhydrous,
Menthol, Polyethylene glycol 400, Aspartame, Passion fruit and
lemon flavours
Methodology
Analytical Methods
Standard Graph of Saxagliptin
Preparation of calibration curve of Saxagliptin
Standard plot of Saxagliptin was prepared using pH phosphate
buffer. 100 mg of Saxagliptin was
weighed and transferred into volumetric flask. To this add small
quantity of pH 6.8 phosphate
buffer to dissolve the drug and then the solution was made up to
100 ml using pH phosphate
buffer. This is stock solution (A). From stock solution (A), 1
ml was transferred into 100 ml
volumetric flask and made up to the mark. This is stock solution
(B). From stock solution (B),
appropriate dilutions 2, 4, 6, 8, 10 were made and absorbance
was measured by using UV-
Spectrophotometer at 208 nm.
Preformulation studies:
Preformulation testing is the first step in the rational
development of dosage forms of a drug
substance. It can be defined as „investigation of physical and
chemical properties of the drug
substance alone and when combined with excipients. These studies
should focus on those
physicochemical properties of the new compound that could affect
drug performance and
development of an efficacious dosage form.(Solubility Analysis
and Melting Point)
Drug-Excipient Compatibility Studies
FTIR interaction studies
Drug-excipient compatibility study was performed by Fourier
transform infrared (FTIR)
Spectroscopy. In the preparation of formulation, the drug and
polymers were in close contact
with each other, which could leads to instability of drug. Thus
preformulation studies regarding
drug-polymer interaction is very important in selecting
appropriate polymers.
Method of preparation of rapidly dissolving films and its
evaluation
Preparation of rapidly dissolving films (RDF)
The RDF of Saxagliptin using various grades of HPMC E LV were
prepared by solvent casting
method. An aqueous solution of the polymer HPMC E LV was
prepared in distilled water.
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2673
Saxagliptin was added to the aqueous polymeric solution. This
was followed by addition of
menthol which was previously dissolved in ethyl alcohol (95%)
and plasticizers like PEG 400 or
glycerol. Sweeteners like aspartame and sucralose were also
added to the above solution. Citric
acid and flavour were also mixed with it. The solution was
casted on a glass petridish (diameter 9
cm) and dried at room temperature for 24 hr.
The film was carefully removed from the petridish, checked for
any imperfections and cut into the
required size to deliver the equivalent dose (2 x 2 cm2) per
strip. The samples were stored in a
desiccator at relative humidity 30-35 % until further analysis.
Film samples with air bubbles, cuts
or imperfections were excluded from the study.
The calculation for the strips of RDF to be prepared is shown
below-
Diameter of petridish = 8.97 cm, Surface area of petridish =
63.34 cm2, Number of strips
obtained =16
Table 1: Composition of Oral Thin Films Contating
Saxagliptin
Ingredi
ents/Ba
tch
F
1
F
2
F
3
F
4
G
1
G
2
G
3
G
4
E
1
E
2
E
3
E
4
E
5
E
6
E
7
E
8
E
9
E
1
0
E
1
1
E
1
2
E
1
3
E
1
4
E
1
5
E1
6
Saxagli
ptin 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5
HPMC
E5 LV
2
0
0
2
0
0
4
0
0
4
0
0
- - - - - - - - - - - - - - - - - - - -
HPMC
E15 LV - - - -
2
0
0
2
0
0
4
0
0
4
0
0
- - - - - - - - - - - - - - - -
HPMC
E3 LV - - - - - - - -
2
0
0
2
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
4
0
0
40
0
Menthol -
7
.
2
-
1
1
.
2
-
7
.
2
-
1
1.
2
- 7.
2 -
1
1.
2
-
1
1.
2
-
1
1.
2
-
1
1.
2
-
1
1.
2
- 2
8
2
8 28
Glycero
l - - - - - - - - - - - -
1
1
2
1
1
2
2
2
4
2
2
4
- - - - - - 5
6
11
2
PEG400 - - - - - - - - - - - - - - - -
1
1
2
1
1
2
2
2
4
2
2
4
5
6
5
6 - -
Asparta
me
(10%)
- - - - - - - - - - - - - - - - - - - - - 5
6
5
6 56
Distilled
Water
(ml)
1
0
1
0
2
0
2
0
1
0
1
0
2
0
2
0
1
0
1
0
2
0
2
0
2
0
2
0
2
0
2
0
2
0
2
0
2
0
2
0
2
0
2
0
2
0 20
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2674
Evaluation of RDF
The RDF were evaluated for the following parameters-
1. Measurement of mechanical properties of the RDF
2. In-vitro disintegration studies
3. In-vitro dissolution studies
4. Environment Scanning electron microscopy (ESEM)
5. Taste evaluation
Measurement of mechanical properties of the film
Mechanical properties of the RDF were evaluated using Lloyd
universal testing machine, UK
with load cell range 0-40 N. Films of dimension 10 x 2.5 cm2 and
free from physical
imperfections were used for the study. The films were held
between two clamps at distance of 5
cm. The RDF were pulled by the clamp at the rate 50 mm/min.
Measurements were done in
triplicate for each batch.
The mechanical properties tensile strength, elastic modulus and
% elongation were calculated for
the RDF from the above measurements.
Tensile strength is the ratio of maximum stress applied to a
point at which the film specimen
breaks and can be computed from the applied force at rupture to
the cross sectional area of the
fractured film as a mean of three measurements and described in
the equation-
Tensile strength = Force at break (N)
Initial cross sectional area of the film (mm2)
Elastic modulus is the ratio of applied stress and corresponding
strain in the region of
approximately linear proportion of elastic deformation on the
load displacement profile and
calculated using the following equation-
Elastic modulus = Force at corresponding strain (N) x 1
Cross-sectional area of the film corresponding strain
Percentage elongation was calculated by the following
equation-
= Increase in length x 100
Original length
Study of Physical properties:
Weight variation:
Three films each of 1 cmwas cut at three different places from
the casted film were taken and
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2675
weighed individually on analytical electronic balance and weight
of each film was noted and
weight variation was calculated. It was found to be in a range
of 53.05±0.43 to 150.68 ± 0.33. The
weight of all the films was found to be uniform. From all the
formulations it has been observed
that increase in concentration of polymer increases weight of
the film. Weight variation is an
important parameter to consider as any variation in the weight
of film leads to under medication or
over medication.
Thickness:
Thickness of films was measured by screw gauge at different
locations. It is essential to
determine uniformity in the thickness of the thickness of the
film as this is directly related to
accuracy of dose in films. The average thickness and standard
deviation were reported.
Moisture Uptake:
The film sample was weighed and placed on a preweighed stainless
steel wire mesh. The wire
mesh was then submerged in a Petri dish containing 20 ml
distilled water. Increase in weight of
the film was determined at regular time intervals until a
constant weight was obtained. The
hydration ratio of the film was calculated using following
formula:
Where,
Wt = Weight of film at time„t‟
W0 = Weight of film at „zero‟ time.
Moisture Loss:
The percent moisture loss was determined by placing prepared
film in desiccators containing
anhydrous calcium chloride. After three days, the film was taken
and reweighed. The percent
moisture loss was calculated using following formula:
Where,
W0= Initial weight
Wt = Final weight.
In-vitro disintegration studies
Disintegration time study was slightly modified to mimic the
in-vitro and in-vivo conditions. For
the study, film as per the dimensions (2 x 2 cm2) required for
dose delivery were placed on a
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2676
stainless steel wire mesh containing 10 ml distilled water. Time
required for the film to break and
disintegrate was noted as in- vitro disintegration time. Since,
the film is expected to disintegrate in
the mouth in presence of saliva, only 10 ml of medium was
used.
In-vitro dissolution studies
The in-vitro dissolution studies were conducted using three
media namely distilled water(500 ml),
simulated gastric fluid (900 ml) and simulated saliva (500 ml).
The dissolution studies were
carried out using USP dissolution apparatus XXIV (Electrolab,
Mumbai, India) at 37 + 0.5°C and
at 50 rpm using specified dissolution media. Each film with
dimension (2 x 2 cm2) was placed on
a stainless steel wire mesh with sieve opening 700μm. The film
sample placed on the sieve was
submerged into dissolution media. Samples were withdrawn at 2,
5, 10, 15, 30, 60, 120 min time
intervals and filtered through 0.45μmWhatman filter paper and
were analyzed
spectrophotometrically at 208 nm (UV 2450Shimadzu, Japan). To
maintain the volume, an equal
volume of fresh dissolution medium maintained at same
temperature was added after withdrawing
samples. The absorbance values were converted to concentration
using standard calibration curve
previously obtained by experiment. The dissolution testing
studies were performed in triplicate
for all the batches.
Environment scanning electron microscopy (ESEM)
The surface morphology of the film forming excipient, drug and
the film was observed using
Environment scanning electron microscope (Philips, XL 30, The
Netherlands). The film sample
was placed in the sample holder and the photomicrographs were
taken using tungsten filament as
electron source and GSE detector at 65x and 350x
magnification.
Taste evaluation
Taste acceptability was measured by a taste panel (n=6) with 10
mg drug and subsequently film
sample containing 10 mg drug held in mouth until disintegration,
then spat out and the bitterness
level was then recorded. The volunteers were asked to gargle
with distilled water between the
drug and film sample administration. The scale for the
bitterness study was as follows:
+ = very bitter,
++ = moderate to bitter,
+++ = slightly bitter,
++++ = tasteless/taste masked
+++++ = excellent taste masking
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2677
RESULTS AND DISCUSSIONS
Analytical Methods
Determination of Saxagliptin:
It was performed in pH 6.8 phosphate buffer.
Fig. 1: λ max of Saxagliptin
The drug solution was subjected to scanning between 200 to 400nm
and absorption maximum
was determined. The λ max of saxagliptin was found as 208nm and
that was selected for analysis.
Standard graph for Saxagliptin in 6.8 pH phosphate buffer at
208nm.
The standard graph of Saxagliptin in pH 6.8 phosphate buffer
showed a good linearity with r2 of
0.9997 in the concentration range of 0-10 µg/ml.
Table 2: Standard graph of Saxagliptin Fig.2: Standard graph of
Saxagliptin
Concentration
(µg/m)
Absorbance
(nm)
0 0
2 0.146
4 0.297
6 0.449
8 0.599
10 0.736
Preformulation studies
Preformulation studies for the selected drug Saxagliptin include
test for identification
(examination of physical appearance, melting point
determination, and IR spectroscopy) and
solubility studies.
Tests for Identifications:
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2678
Physical appearance: Saxagliptin was found to be a white to off
white crystalline powder, non-
hygroscopic in nature.
Melting point: Saxagliptin was found to be melting at 228°C
Solubility Analysis:
A definite quantity (5 mg) of drug was dissolved in 5 ml of each
solvent at room temperature. The
solubility was observed only by the visual inspection.
Table 3
S.No Solvents Solubility
1 Distilled water Sparingly soluble
2 Ethyl acetate Slightly soluble
3 Methanol, ethanol, IPA, Acetonitrile; PEG 400 Soluble
Drug Compatibility Studies
FT-IR-spectra: The characteristic peaks were determined by FT-IR
spectra, which identified the
purity of drug.
Compatibility Studies:
FTIR interaction studies.
As described in the methodology section, drug- polymer
compatibility studies were carried out
using Fourier Transform Infrared Spectroscopy to establish any
possible interaction of Saxagliptin
with the polymers used in the formulation. It was expected that
the intermolecular hydrogen
bonding between hydroxyl groups of HPMC and amino (-NH) groups
of Saxagliptin might be
involved. In order to have better understanding of type of
interaction between the blended
polymers, FTIR spectra of all different combinations of polymers
with the drug were studied.
The results indicated that the characteristic absorption peaks
due to pure Saxagliptin have
appeared in the formulated FDF‟s, without any significant change
in their position after
successful formulation, indicating no chemical interaction
between Saxagliptin and polymers.
Fig. 3: FTIR Spectra Saxagliptin
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2679
Fig. 4: FTIR Spectra of optimized formulation
Preliminary trials
The preliminary trials were undertaken for designing the RDF
wherein the effects of various
grades of HPMC namely E3, E5 and E15 LV on the characteristics
of the films were assessed. All
the three grades were varied in a concentration range of 1 to 4%
w/v. Initial trials were taken to
check the suitability of various grades of HPMC E LV for the
formation of RDF without addition
of the drug. In-vitro disintegration time studies as shown in
Table 7.3 suggested that films
prepared using all 3 grades of HPMC E LV had in-vitro
disintegration time below 30 sec and was
thus, acceptable for further formulation.
Table 4: In-vitro disintegration time of blank preliminary
batches
In-Vitro Disintegration Time (Sec)
Grade/Concentration 1% 2% 3% 4%
HPMC E3 LV 7.5 (1E) Very Thin, Brittle 12.5 (2E) 12.5 (3E)
22.5(4E)
HPMC E5 LV 7.5 (1F) Very Thin, Brittle 12.5 (2F) 25 (3F)
25(4F)
HPMC E15 LV 12.5 (1G) Very Thin, Brittle 17.5 (2G) 25 (3G)
30(4G)
Figures in bracket indicates batch number; n=3.
Films prepared at 1% w/v concentration using all the three
grades were very thin, brittle and were
easily broken. Films with 2% to 4% w/v concentration for all
three grades were clear, transparent
and easily separated. Therefore, further batches containing the
drug were formulated using 2% to
4% w/v of HPMC E LV grades.
Table 5: Preliminary trials using HPMC E5 LV as a polymer
Ingredients*/Batch F1 F2 F3 F4
Saxagliptin 5 5 5 5
HPMC E5 LV 200 200 400 400
Menthol - 7.2 - 11.2
Distilled Water (ml) 10 10 20 20
In-Vitro Disintegration Time (Sec) - - 45 45
Film Property Brittle, Very Thin Brittle, Very Thin Good
Good
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2680
*All quantities are in mg, Batch size 16 strips
The RDF containing 200 mg HPMC E5 LV formulated with Saxagliptin
resulted in highly brittle
films compared to films containing 400 mg HPMC E5 LV which were
separated easily. Thus,
films containing 400 mg HPMC E5 LV were further evaluated for
various parameters. The reason
for the brittle film formation in the presence of the drug using
200 mg HPMC E5 LV might be
insufficient amount of sample required for film formation. The
in-vitro disintegration time of
batches containing 400 mg HPMC E5 LV was acceptable i.e. 45 sec.
Trials were also taken with
the same formulation in presence (containing 0.7 mg menthol per
strip) and absence of menthol as
a cooling agent.
Table 6: In-vitro dissolution profile of batch F3 and F4 in
distilled water
Time (min) Cumulative % Drug release
F3 F4
0 0 0
2 59.01 60.72
5 75.51 70.66
8 92.62 89.98
10 100 85.64
15 - 96.77
30 - 100
60 - -
In-vitro dissolution study of batch F3 and F4 was carried out in
distilled water. It was observed
that complete drug released in 10 min and 30 min respectively
for batch F3 and F4.
Table 7: Formulation trials containing HPMC E15 LV as a
polymer
Ingredients*/Batch G1 G2 G3 G4
Saxagliptin 5 5 5 5
HPMC E15 LV 200 200 400 400
Menthol (2%) - 7.2 - 11.2
Distilled Water (ml) 10 10 20 20
In-Vitro Disintegration Time (Sec) 45 45 95 95
Film seperation Good Good Good Good
*All quantities are in mg, Batch size 16 strips
G1 to G4 containing HPMC E 15 LV as a film forming polymer. The
RDF containing 200 mg
HPMC E15 LV formulated with Saxagliptin resulted in films with
good quality and acceptable in-
vitro disintegration time (45 sec). Films with 400 mg HPMC E15
LV resulted in higher in-vitro
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2681
disintegration time (95 sec). This might be due to delayed
disintegration time with higher
viscosity grade of HPMC E LV at higher concentrations.
Table 8: In-vitro dissolution profile of batch G1, G2, G3 and
G4
Time (min) Cumulative % drug release
G1 G2 G3 G4
0 0 0 0 0
2 67.63 69.26 63.95 71.78
5 76.95 73.3 69.36 77.93
8 86.02 81.8 75.55 85.98
10 91.57 90.44 82.34 89.34
15 96.24 93.86 83.06 94.96
30 100 96.53 83.17 95.93
60 99.89 100 89.51 98.52
120 - - 84.86 92.12
240 - - 100 100
Table shows in-vitro dissolution profile of batches G1 to G4.
Batches G1 and G2 showed 67-69%
drug release in 2 min and 96% and 94% drug release in 15 min but
as the amount of HPMC E15
LV was increased, drug release was retarded and complete drug
release was observed in 4 hr.
Thus, HPMC E15 LV retarded the dissolution behaviour of rapidly
dissolving films.
Table 9: Formulation trials containing HPMC E3 LV as a
polymer
Ingredients*/Batch E1 E2 E3 E4
Saxagliptin 5 5 5 5
HPMC E3 LV 200 200 400 400
Menthol - 7.2 - 11.2
Distilled Water (ml) 10 10 20 20
Total weight/Strip 22.5 22.95 35 35.7
Film separation No No No Partial
*All quantities are in mg, Batch size 16 strips
Saxagliptin when incorporated in 200 mg of HPMC E3 LV films
resulted in formation of very
brittle and thin films. When Saxagliptin was incorporated in 400
mg of HPMC E3 LV, it resulted
in slightly brittle films. Thus, to improve the characteristics
of the film addition of plasticizer was
found to be necessary. Various preliminary formulations E5 to
E12 using 400 mg HPMC E3 LV
were prepared to check film separation property using glycerol
and menthol as plasticizer.
Table 10: Formulation batches with HPMC E3 LV using glycerol
Ingredients*/Batch E5 E6 E7 E8
Saxagliptin 5 5 5 5
HPMC E3 LV 400 400 400 400
Menthol (2%) - 11.2 - 11.2
Glycerol 112(0.2:1) 112 224(0.4:1) 224
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2682
PEG400 - - - -
Distilled Water (ml) 20 20 20 20
Total weight/Strip 42 42.7 42 42.7
Film seperation No No No Yes
*All quantities are in mg, Batch size 16 strips
None of the above batches resulted in good film separation
property. So, further trials were
carried out using PEG 400 as plasticizer.
Table 11: Formulation batches with HPMC E3 LV using PEG 400
Ingredients*/Batch E9 E10 E11 E12
Saxagliptin 5 5 5 5
HPMC E3 LV 400 400 400 400
Menthol (2%) - 11.2 - 11.2
Glycerol - - - -
PEG400 112 (0.2:1) 112 224(0.4:1) 224
Distilled Water (ml) 20 20 20 20
Film seperation Yes Yes Yes, soft Partial
Invitro disintegration time (Sec) 60 60 - -
*All quantities are in mg, Batch size 16 strips
PEG 400 at (plasticizer: polymer) ratio of 0.2:1 resulted in
better elasticity than glycerol. Thus, it
could be concluded that film separation could be improved in the
presence of plasticizer PEG
400. In-vitro dissolution study of batch E9 was carried out in 3
different dissolution media as
shown in Table 7.10.
Table 12: In-vitro dissolution study of batch E9
The in-vitro disintegration time of batch E9 containing 400 mg
HPMC E3 LV, Saxagliptin and
PEG 400 was 25 sec. The comparative drug release of batch E9 in
different dissolution medium
Time (Min)
Cumulative % Drug Release
Batch E9
PH 6.8 Phosphate Buffer 0.1N HCl Simulated Saliva
0 0 0 0
2 85.3 80.61 78.22
5 100 83.35 82.23
8 - 82.89 88.96
10 - 86.65 93.12
15 - 100 100
30 - - -
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2683
indicated 85% drug release in 2 min in pH 6.8 Phosphate Buffer,
81% drug release in 2 min in
0.1N HCl and 78% drug release in 2 minutes in simulated
saliva.
Fig. 5: Comparative in-vitro dissolution profile of batch E9
Thus, it can be concluded that the viscosity grades of HPMC E LV
affected the mechanical
properties, disintegration and dissolution characteristics of
the RDF. The higher the viscosity of
HPMC E LV grades, there was an increase in the in-vitro
disintegration and dissolution time.
Although batches containing 400 mg HPMC E5 LV and 200 mg HPMC
E15 LV in presence of
drug had an in-vitro disintegration time of 45 sec, the in-vitro
dissolution time was 30 min and 45
min in distilled water respectively. Batch E9 had 98% drug
release in 2 min in distilled water.
Therefore, further studies were carried out using HPMC E3 LV as
a polymer for the RDF
formulation trials. RDF containing Saxagliptin prepared using
HPMC E3 LV also possessed
satisfactory mechanical property, in-vitro disintegration and
in-vitro dissolution time and were
used for further optimization.
Taste masking of Saxagliptin films
Saxagliptin being bitter in taste, the taste masking of the
films was found to be essential to
improve the patient acceptability. To improve the taste of the
films, flavours and sweeteners were
incorporated in the formulation. Various amount of menthol (5%
w/w of drug and polymer
amount) and sucralose (10%w/w of drug and polymer amount) at
various plasticizer ratios were
added to Saxagliptin containing films.
Table 13: Formulation batches with HPMC E3 LV
Ingredients/Batch E13 E14 E15 E16
Saxagliptin 5 5 5 5
HPMC E3 LV 400 400 400 400
Menthol (5%) - 28 28 28
Aspatame (10%) - 56 56 56
Flavour - - Yes Yes
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2684
Glycerol - - 56 112
PEG400 56 56 - -
Distilled Water (ml) 20 20 20 20
Total Weight/Strip 38.5 42.7 42 42.7
Film Separation -- -- No, Film Too soft No, Film Too soft
None of the above batches resulted in taste masking of the film.
Thus, further trial batches S1 to
S4 were taken with another sweetener sucralose. This too did not
result in taste masking of
Saxagliptin. As none of the above excipients resulted in
complete taste masking of the film
further trials were taken using combination of sweeteners i.e.
aspartame and sucralose.
Table 14: Selection of sweetener for the taste masked films
Ingredients/Batch S1 S2 S3 S4
Aspartame - - - 112
Sucralose 84 84 56 84
PEG400 - 112 112 112
Film Separation No yes Partial Yes
Invitro disintegration time(sec) 25 25 25 50
Taste Masking ++ ++ ++ +++
*All quantities are in mg, Batch size 16 strips
All batches contained 400 mg HPMC E3 LV and 5 mg Saxagliptin.
All batches were formulated
in 20 ml distilled water.
Table shows that batch S4 exhibited an in-vitro disintegration
time of 50 sec. The batch S4
possessed good taste masking property but was followed by bitter
aftertaste.
Table 15: In-vitro dissolution of batch S4 in pH6.8 phosphate
buffer, 0.1N HCl and
simulated saliva
Time (Min)
Batch S4
Cumulative % release in different medium
pH 6.8 Phosphate buffer 0.1N HCl Simulated Saliva
0 0 0 0
2 77.24 90.65 79.25
5 82.57 90.89 83.43
8 83.09 92.03 89.24
10 84.89 100 95.45
15 86.48 -- 98.38
30 90.65 -- 100
60 100 -- --
In-vitro disintegration time of batch S4 was found to be 20 sec.
In-vitro dissolution study of batch
S4 in 3 different dissolution media distilled water, 0.1N HCl
and simulated saliva is shown in
Table. In-vitro dissolution study of batch S4 in 3 different
dissolution media pH 6.8 phosphate
buffer , 0.1N HCl and simulated saliva is shown.
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2685
Fig. 6: In-vitro dissolution study of batch S4 in 3 different
dissolution media pH 6.8
Phosphate Buffer, 0.1N HCl and simulated saliva
Thus, formulation trials were carried out by using flavouring
agents such as lemon and passion
fruit flavour and sour ingredients like citric acid.
Table 16: Selection of flavour for the taste masked films
Ingredients/Batch T1 T2 T3 T4
Flavour Passion fruit Lemon Passion fruit Lemon
PEG400 56 56 112 112
Citric acid 140 140 140 140
Film Separation Partial Yes Yes Yes
In-vitro disintegration time(sec) 50 50 50 50
Elasticity Good Good Very good Very good
Taste masking +++ ++ ++++ ++
*All quantities are in mg, Batch size 16 strips
All batches were formulated contained 400 mg HPMC E3 LV, 5 mg
Saxagliptin, 112 mg
aspartame and 84 mg sucralose in 20 ml distilled water. Table
indicates that further addition of
flavouring agents like citric acid and passion fruit flavour (T1
to T4) resulted in completely taste
masked film of batch T3. The in-vitro disintegration time was 50
sec. In-vivo disintegration time
of batch T3 was 20 sec. Addition of lemon flavour (T2 and T4)
resulted in highly acidic taste of
the film which was unacceptable. Batch T3 showed good elasticity
and taste masking properties.
In-vitro dissolution profile of batch T3 in different
dissolution media i.e. Phosphate buffer
6.8pH,0.1N HCl and simulated saliva is shown Table 7.15.
Table 17: In-vitro dissolution profile of batch T3 in pH6.8
Phosphate buffer , 0.1 N HCl and
simulated saliva
Time (min)
Batch T3
Cumulative % release in different medium
Phosphate buffer 6.8pH 0.1N HCl Simulated saliva
0 0 0 0
2 100 95 80.31
5 - 98 86.27
8 - 98.5 91.16
10 - 100 95.86
15 - - 100
30 - - -
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2686
Fig.7: Comparative in-vitro dissolution study profiles of batch
T3
Figure indicates the comparative in-vitro dissolution profile of
batch T3 in different dissolution
medium. It can be concluded from the Figure that in 2 min batch
T3 showed 100% drug release in
pH 6.8 Phosphate Buffer, 98% in 0.1N HCl and 80% in simulated
saliva.
Environment scanning electron microscopy (ESEM)
The ESEM of HPMC E3 LV shown in Figure7.8 indicated irregular
cylindrical to spherical
shaped particles at 150x magnification. Saxagliptin particles
could not be seen distinct as such.
On dispersing it in acetone as shown in Figure7.9 cylindrical
distinct particles could be observed
at 350x magnification. Figure 7.10 indicates optimized film at
350x magnification which was
uniform with few pores and solid particles without any
striations.
Fig. 8: ESEM of HPMC E3 LV powder Fig.9: ESEM of Saxagliptin
powder
at 150x magnification at 350x magnification
Fig. 10: ESEM of T3 film at 350x magnification
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2687
Study of mechanical properties
A suitable RDF requires moderate tensile strength, good
percentage elongation and low elastic
modulus.
Table 18: Comparative mechanical properties of various
batches
Batch Tensile Strength (N/mm2) % Elongation Elastic Modulus
(N/mm2)
2E 19.49 1.82 654.6
4E 23.38 2.81 406.6
E9 9.07 8.55 162
S4 8.65 21.64 163
T3 4.22 27.69 38
Table shows the comparative mechanical properties of various
formulations prepared during the
study. It can be observed that RDF containing 2% and 4% HPMC E3
LV alone i.e. batches 2E
and 4E showed extremely high tensile strength, poor % elongation
values and very high elastic
modulus. The same formulation in the presence of drug and
plasticizer (E9) demonstrated lower
tensile strength compared to batch 2E and 4E. The % elongation
values increased and elastic
modulus values decreased. The taste masked batches S4 and T3
were found to possess acceptable
mechanical properties. The tensile strength values were in
moderate range (4-9 N/m2). The %
elongation (21-28) and elastic modulus (35-165) were also
satisfactory. These changes in the
mechanical properties can be attributed to the presence of
plasticizer in the batches E9, S4 and T3.
Compared to films containing pullulan, HPMC E3 LV films
possessed higher % elongation and
lower elastic modulus. The low % elongation value indicates
brittle nature of the pullulan film.
Higher elastic modulus values indicate more toughness of
pullulan containing films compared to
HPMC E3 LV films. Batch T3 showed most acceptable mechanical
properties along with
complete taste masking which might be due to presence of
suitable plasticizers and flavours.
Batch T3 showed most acceptable mechanical properties along with
complete taste masking
which might be due to presence of suitable plasticizers and
flavours.
Study of Physical properties:
Weight variation:
Three films each of 1 cmwas cut at three different places from
the casted film were taken and
weighed individually on analytical electronic balance and weight
of each film was noted and
weight variation was calculated. It was found to be in a range
of 53.05±0.43 to 150.68 ± 0.33. The
weight of all the films was found to be uniform. From all the
formulations it has been observed
that increase in concentration of polymer increases weight of
the film. Weight variation is an
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2688
important parameter to consider as any variation in the weight
of film leads to under medication or
over medication.
Table 19: Comparative Physical properties of various batches
Batch Thickness (µm)* Mean Weight (1*1 Film)
(mg)*
% Moisture
Uptake
% Moisture
Loss
2E 0.3±0.01 53.05 ± 0.43 12.87 0.90
4E 0.5±0.01 104.89 ± 0.12 25.7 0.33
E9 0.8±0.02 101.5 ± 0.53 21.58 0.28
S4 1.1±0.01 150.68 ± 0.33 21.79 0.74
T3 1.3±0.01 136.22±0.14 19.57 0.75
* Mean ± SD; n = 3
Moisture absorption:
Moisture absorption study was performed to check the physical
integrity of films. The films were
weighed accurately and placed on a preweighed stainless steel
wire mesh. The wire mesh was
then submerged in a Petri dish containing 20 ml distilled water.
Increase in weight of the film was
determined at regular time intervals until a constant weight was
obtained.
Moisture absorption study is an important parameter to be
performed, as the presence of
moisture possesses a critical challenge on drug stability.
Moisture accelerates the hydrolysis of
drug as well as facilitates reaction with other excipients,
thereby affecting stability and shelf life of
the final dosage form. All the reported values were shown. And
it has been observed that all the
film forming polymers HPMC E3LV, E5LVand E15LV were of
hydrophilic in nature and the
obtained values were in a range of 12.87 to 25.7%.
Moisture loss:
Moisture loss study was performed to check physical stability of
films at dry environment. Film
was weighed accurately and kept in desiccator containing
anhydrous calcium chloride for 3 days
and films were removed and reweighed and moisture loss was
calculated. The moisture loss study
gives an idea about films stability nature and ability of films
to withstand its physicochemical
properties under normal conditions. It also gives an idea about
hydrophilicity of film
formulations.
All the obtained values were reported. The obtained values were
in a range of 0.28to 0.90.
Stability studies
The stability studies of the optimized batch T3 was carried out
at 40°C/75%RH, 25°C/60%RH
and 25°C/40%RH. These films were found to be unacceptable. Films
stored at 40°C/75%RH were
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2689
highly unstable within 1 month storage. Films stored at
25°C/60%RH were unstable after 2
months period by developing colour change (yellow) and becoming
sticky in appearance. Films
stored at 25°C/40%RH were found to be stable for one year
period. The batch was found be
acceptable visually, mechanically, with slight change in
in-vitro and in-vivo disintegration time
55 sec, 22 sec respectively. The above observations indicate
that temperature and humidity plays
a critical role in the stability of the rapidly dissolving films
containing HPMC E3 LV as the film
forming polymer. Therefore, precautions would be required during
packaging and selection of
packaging container would play a crucial role for stability of
the RDF.
Table 20: Stability studies of optimized batch
Time
% of drug
dissolved in 2 min
(Distilled water)
In vitro
disintegration
time (sec)
In vivo
disintegration
time (sec)
Appearance
Initial 100 50 20 Transparent, white,
Acceptable
1Month 100 50 21 Transparent, white,
Acceptable
2Months 99 48 20 Transparent, white,
Acceptable
3Months 99 49 21 Transparent, white,
Acceptable
CONCLUSION
Rapidly dissolving films using different grades of HPMC E LV
were formulated using
Saxagliptin. It was formulated especially suitable for pediatric
and geriatric patients. An ideal
rapidly dissolving drug delivery system should have following
properties Transportability, Ease
of handling and administration, No special packaging material
and/or processing requirements,
No water necessary for application and pleasant taste. It was
prepared by solvent casting
method.It was observed that type of grade of HPMC E 3 LV
significantly contributed to in-vitro
disintegration and in-vivo dissolution. Higher viscosity grade
of HPMC E increased in-vitro
disintegration and in-vitro dissolution. HPMC E 3 LV was found
to be suitable polymer for the
formation of rapidly dissolving films. As Saxagliptin is being
bitter in taste, taste masking using
combination of sweeteners, flavours and citric acid was used.
The optimized batch had acceptable
characteristics which include mechanical properties, in-vitro
disintegration time is 25 sec, in-vitro
dissolution drug release 100% in 2 min and taste masking
properties. ESEM study was also
carried out to study the surface morphology. These present
findings suggest that the formulation
contaning Saxagliptin developed disintegrate within a minute
hence is potentially useful for
-
RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014,
2669-2690
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2690
pediatric and geriatric patients who show unwillingness to take
tablets. It can be concluded that
the RDF of Saxagliptin which can be a promising drug delivery
system.
REFERENCES
1. Arnum PV, “Outsourcing solid dosage manufacturing”, Pharm
Tech, 30(6), 44-52, June
2006.
2. Pfister W, Ghosh T, Intraoral delivery systems: An overview,
current status and future
trends. In Tapash Ghosh, William Pfister (Ed.), Drug Delivery to
the Oral eavity:
Molecules to Market (pp.1 -34). Florida: eRe Press, Taylor &
Francis gp, 2005.
3. Pfister W, Ghosh, T, ehatterJee D, Jarugula V, Fadiran E,
Hunt J, Lesko L, Tammara V,
Hare D, Quick dissolving oral dosage forms: Scientific and
regulatory considerations from
a clinical pharmacology and biopharmaceutics perspective. In
Tapash Gh osh, William
Pfister (Ed.), Drug Delivery to the Oral eavity: Molecules to
Market (pp.337-353).
Florida: eRe Press, Taylor & Francis gp, 2005.
4. Liang AC, Chen LH, "Fast Dissolving Intraoral Drug Delivery
Systems", Exp. Opin. Ther.
Patents, 11(6), 981-986, 2001.
5. Mishra R, Amin A, "Quick API Delivery," Pharm Tech (Europe),
19(10), 35-39, 2007.
6. Mishra R, Amin A, "Formulation development of taste masked
rapidly dissolving films of
cetirizine hydrochloride", Pharm Tech (USA), 33(2), 48-56,
2009.
7. Vondrak B, Barnhart S, "Dissolvable films for flexible
product format in drug delivery".
Pharma Technol., Suppl, S20 -28, 2008.
8. Barnnart S, Sloboda M, "Dissolvable films-The future of
dissolvable films", Drug Del
Tech, 7(8), 34-37, Sept 2007.
9. www.inpharmatechnologist.com, Novartis launches first
systemic OTe in film strip format
10. www.nmafaculty.org/news/thin_strip.htm, Pharmacist
counseling can prevent
unintentional errors with thin strip dosage forms
11. Arnum PV, "Outsourcing solid dosage manufacturing", Pharm
Tech, 30(6), 44-52, June
2006.
12. Corniello CM, "Quick dissolve films Quick -Dissolve strips:
From concept to
commercialization", Drug Delivery Technology, 6(2), Feb
2006.