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Drug Delivery
ISSN: 1071-7544 (Print) 1521-0464 (Online) Journal homepage: http://www.tandfonline.com/loi/idrd20
In vitro/in vivo evaluation of an optimized fastdissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylicacids
Eman Magdy Maher, Ahmed Mahmoud Abdelhaleem Ali, Heba FaroukSalem & Ahmed Abdelbary Abdelrahman
To cite this article: Eman Magdy Maher, Ahmed Mahmoud Abdelhaleem Ali, Heba FaroukSalem & Ahmed Abdelbary Abdelrahman (2016): In vitro/in vivo evaluation of an optimized fastdissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylicacids, Drug Delivery, DOI: 10.3109/10717544.2016.1153746
To link to this article: http://dx.doi.org/10.3109/10717544.2016.1153746
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Drug Deliv, Early Online: 1–13! 2016 Taylor & Francis. DOI: 10.3109/10717544.2016.1153746
RESEARCH ARTICLE
In vitro/in vivo evaluation of an optimized fast dissolving oral filmcontaining olanzapine co-amorphous dispersion with selectedcarboxylic acids
Eman Magdy Maher1, Ahmed Mahmoud Abdelhaleem Ali1,2, Heba Farouk Salem1, andAhmed Abdelbary Abdelrahman3
1Department of Pharmaceutics, Faculty of Pharmacy, Beni Suef University, Beni Suef, Egypt, 2Department of Pharmaceutics, Faculty of Pharmacy,
Taif University, Taif, Saudi Arabia, and 3Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Abstract
Improvement of water solubility, dissolution rate, oral bioavailability, and reduction of first passmetabolism of OL (OL), were the aims of this research. Co-amorphization of OL carboxylic aciddispersions at various molar ratios was carried out using rapid solvent evaporation.Characterization of the dispersions was performed using differential scanning calorimetry(DSC), Fourier transform infrared spectrometry (FTIR), X-ray diffractometry (XRD), and scanningelectron microscopy (SEM). Dispersions with highest equilibrium solubility were formulated asfast dissolving oral films. Modeling and optimization of film formation were undertaken usingartificial neural networks (ANNs). The results indicated co-amorphization of OL-ascorbicacid through H-bonding. The co-amorphous dispersions at 1:2 molar ratio showed more than600-fold increase in solubility of OL. The model optimized fast dissolving film prepared fromthe dispersion was physically and chemically stable, demonstrated short disintegration time(8.5 s), fast dissolution (97% in 10 min) and optimum tensile strength (4.9 N/cm2). The results ofin vivo data indicated high bioavailability (144 ng h/mL) and maximum plasma concentration(14.2 ng/mL) compared with the marketed references. Therefore, the optimized co-amorphousOL-ascorbic acid fast dissolving film could be a valuable solution for enhancing thephysicochemical and pharmacokinetic properties of OL.
Keywords
Amorphous, bioavailability, fast dissolvingfilm, neural networks, olanzapine,pharmacokinetics, solid dispersion
History
Received 9 December 2015Revised 4 February 2016Accepted 9 February 2016
Introduction
Typical antipsychotic drugs are usually classified by their
chemical structure and the potency of binding to the
dopamine type 2 (D2) receptors, while new antipsychotic
agents differ from selective dopamine antagonist in having a
broader receptor affinity and hence called atypical antipsych-
otics. The atypical antipsychotics are characterized by
improved clinical efficacy against schizophrenia and bipolar
disorders with fewer side effects such as hallucinations and
delusions (Worrel et al., 2000). These are also better than the
typical analogs at relieving the negative symptoms of the
illness, such as withdrawal, thinking problems, and lack of
energy (Ayala et al., 2006). Olanzapine (OL) is one of the
recent atypical antipsychotics that belongs to the thienoben-
zodiazepine-class(2-methyl-4-(4-methyl-1-piperazinyl)-10H-
thieno-[2,3-b][1,5] benzodiazepine) (Ayala et al., 2006). It is
widely used in the treatment of schizophrenia and acute
mixed or manic episodes. It is highly efficient with no or
minimal side effects such as weight gain and agranulocytosis
being similar to the first line treatment such as clozapine
(Volavka et al., 2004). However, OL exhibits very slight
solubility in water and suffers from extensive first pass
metabolism and, therefore, possesses low bioavailability
(40%) after oral administration (Sood et al., 2013).
Numerous trials were reported in the literature for improving
bioavailability of OL using solid lipid nanoparticles or
through formation of solid dispersions with various polymeric
carriers (Krishnamoorthy et al., 2009; Harde et al., 2011;
Cavallari et al., 2013; Sood et al., 2013).
Intraoral fast dissolving films (FDF) are non-bulky oral
dosage forms that have several advantages over conventional
oral dosage forms including the ease of administration with no
need for water thus improving patient compliance particularly
elderly and pediatrics. It also enables availability of larger
surface area that leads to rapid disintegration and release of
the drug into the oral cavity within seconds and hence a rapid
onset of action could be achieved (Liang & Chen, 2001; Dixit
& Puthli, 2009; Hoffmann et al., 2011). Owing to pregastric
or oro-mucosal absorption, drugs can directly enter systemic
circulation avoiding first-pass metabolism thus improving
bioavailability with possibility of reduced dosing and fewer
side effects (Saurabh et al., 2011). Many studies on
orodispersible polymer films have been conducted for various
reasons; as enhancing solubility of poorly soluble BCS class
Address for correspondence: Ahmed Mahmoud Abdelhaleem Ali,Department of Pharmaceutics, Faculty of Pharmacy, Taif University,Saudi Arabia. Email: [email protected]
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II drugs, taste masking of antihistamines, or increasing
patient compliance for administration of antidepressant
drugs (El-Setouhy & El-Malak, 2010; Preis et al., 2012;
Sievens-Figueroa et al., 2012). Optimized formulations of
orodispersible polymer films were also studied in the
literature using simple methodologies such as solvent casting,
hot-melt extrusion, and freeze drying (ElMeshad & El
Hagrasy, 2011; Low et al., 2013; Kumria et al., 2016;
Shamma & Elkasabgy, 2016). The aim of the current study
was to improve the dissolution properties of the poorly water-
soluble OL via formation of stable OL co-amorphous
dispersions (COADs) from successful solid dispersions with
some polycarboxylic acids (CAPs) (Ali et al., 2015). Solid
dispersion method adjustment could result in co-amorphiza-
tion of the active pharmaceutical ingredients using numerous
coformers and many successful examples were employed in
the pharmaceutical research for improving the physicochem-
ical properties especially for poorly soluble drugs (Jensen
et al., 2015; Qian et al., 2015). Co-milling and freeze drying
with hydrophilic polymers were used to form amorphous
glass solutions and hot-melt extrusion of drugs using mixtures
of low-melting polymers and surfactants were also employed
for co-amorphization (Zhang et al., 2014). Some di and tri-
carboxylic acids have the ability to adjust the glass transition
temperature of the composite solid dispersion by the
antiplasticizing effects thus protecting the amorphous state
of the resulting dispersion (Curtin et al., 2012). In this study,
solvent evaporation under vacuum was used for the prepar-
ation of solid dispersions of OL and poly carboxylic acids
followed by incorporation of successful co-amorphous dis-
persions into different film formulations, followed by incorp-
oration in different film formulations. Modeling and
optimization of the effects of film formulation parameters
on its mechanical strength, disintegration, and dissolution
properties were extensively studied using response surface
models (Hosny et al., 2016). However, in this work, modeling
was undertaken using artificial neural networks and genetic
algorithms (Abdelrahman et al., 2015). Oral bioavailability
and pharmacokinetics of OL from the optimized fast
dissolving films (OFDF) were evaluated in human volunteers
in comparison with marketed products of OL.
Materials and method
Materials
Olanzapine was obtained as a free sample from the Egyptian
Pharmaceutical Industries Company (EPICO, Cairo, Egypt).
Hydroxy propyl methyl cellulose (HPMC-E5) and sodium
carboxy methyl cellulose (NaCMC) were purchased from
Sigma-Aldrich, Darmstadt, Germany. Glycerol, menthol,
propylene glycol, anhydrous carboxylic acids (CAPs); ascor-
bic acid, tartaric acid, and citric acid were purchased from
Natco Pharma, Hyderabad, India. Ethanol (95%) and acetone
were purchased from El-Gomhoria Company (Cairo, Egypt).
Methanol HPLC grade was purchased from Sigma Aldrich,
Gillingham, UK. Other chemicals were of analytical grade
and were used as obtained.
Preparation of OL/carboxylic acid solid dispersions
Solid dispersion preparation was carried out using fast solvent
evaporation under reduced pressure according to a reported
method (Ali et al., 2015). The calculated equivalent amounts
of anhydrous CAPs, ascorbic, citric and D-tartaric acid
according to molar ratios (Table 1), were dissolved in ethanol
95% (10 mL). The weighted amounts of OL (200 mg) were
dissolved in acetone (10 mL) and then mixed with the
ethanolic solution of CAPs in a rotary evaporation flask.
The flask contents were sonicated for 10 min in a water bath
sonicator (Ultrasonic Cleaner Model 57 H, Ney Instruments
Co. Ltd, Melville, NY) until all contents were completely
dissolved. The resulting solution was evaporated under
vacuum (0.25 MPa) using arotary evaporator (Barloworld
Scientific Ltd., Stone, UK). The water bath temperature was
kept at 50 �C. After complete dryness, the collected mass was
pulverized and passed through sieve number 60 (250 mm
apertures), then kept in a desiccator until further examination.
Characterization of OL-carboxylic acid soliddispersions
Saturated solubility
Saturated solubility of the dispersions was measured by
adding known excess amount of each formula to the
dissolution medium (10 mL). The dispersion was kept in a
shaking water bath (37 �C) for 24 h. The samples were taken
out of the shaker and left aside for an extra 12 h to equilibrate
then filtrated using membrane filter (0.45mm, Millipore�,
Billerica, MA). The filtrate was analyzed spectrophotomet-
rically at lmax 273 nm (Seju et al., 2011).
Scanning electron microscopy (SEM)
The morphology of the prepared dispersions was examined
using SEM (Analytical Scanning Microscope, JEOL-JSM-
6510LA, JEOL, Tokyo, Japan). Few specks from each
formulation were placed on the carbon stubs and then
coated using a gold sputter (SPI-Module Sputter Coater, SPI
Supplies Inc., West Chester, PA) followed by microscopical
scanning.
Table 1. Composition of OL-carboxylic acid solid dispersions.
Formula Olanzapine (mg) Ascorbic acid (mg) Citric acid (mg) Tartaric acid (mg) Stoichiometric ratio
Mr 312.44 176.12 192.12 150.09 –F1 200 112.74 – – 1.00:1.00F2 200 225.48 – – 1.00:2.00F3 200 – 122.98 1.00:1.00F4 200 – 245.96 1.00:2.00F5 200 – – 96.08 1.00:1.00F6 200 – – 192.16 1.00:2.00
2 E. M. Maher et al. Drug Deliv, Early Online: 1–13
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Differential scanning calorimetry (DSC)
DSC analysis of pure OL, CAPs, physical mixtures, and the
prepared dispersion formulations (5 mg) were carried out
using DSC (TA-60WSI, Shimadzu, Tokyo, Japan). The
instrument was calibrated using purified Indium (99.99%).
Samples were sealed in a flat bottom aluminum pan
(Shimadzu DSC-60, Tokyo, Japan). The pan was placed in
the DSC instrument and scanned between 30 and 300 �C at a
rate of 10 �C/min. Dry nitrogen was used as a carrier gas
to eliminate the oxidative and pyrrolytic effects with a
flow rate of 10 mL/min. The melting and transition point
measurements were performed using the software provided
with the device.
Fourier transform infrared analysis (FTIR)
Sample (5 mg) of OL, CAPs, and prepared dispersions were
individually mixed with 100 mg dry potassium bromide. The
powder mixtures were compressed into discs under a pressure
of 10 000–15 000 PSI. The infrared spectrum was determined
at a scanning range of 400–4000 cm�1 using a Fourier
Transform Infrared instrument (IR435-U-04, Shimadzu,
Kyoto, Japan).
X-ray diffraction (XRD)
Samples of OL powder, CAPs as well as the solid dispersion
formulations were subjected to X-ray diffraction analysis
using Shimadzu XRD-6000 X-ray powder diffractometer
(XRD-610, Shimadzu, Tokyo, Japan). The equipment was
coupled with a standard Cu sealed X-ray tube with 40 kV
voltage and 30 mA current (Ali et al., 2015). Data collection
was performed at 2� 5–80� in steps of 0.05� and a scanning
speed of 0.5 s per step.
Preparation of OL fast dissolving films (FDF)
Solvent casting method was adopted for the preparation of
OL FDF using mixtures of the successful co-amorphous
dispersions (COADs) with film-forming polymers, hydroxyl
propyl methyl cellulose (HPMC) and sodium carboxy
methyl cellulose (Na–CMC) as shown in Table 2.
Glycerin, propylene glycol (PG), or PEG 400 were used as
plasticizers, citric acid as saliva stimulant, Na-saccharine as
sweetening agent, and menthol as flavoring agent. The film-
forming polymer was dissolved in cold water then OL
co-amorphous dispersion (COAD) was added in the required
quantity. Menthol was dissolved in 1 mL ethanol, and then
added to the aqueous dispersion. The mixture was kept
under magnetic stirring at room temperature until complete
dissolution. Before film casting, the aqueous solution was
sonicated for 1 h to ensure complete removal of the
entrapped air bubbles. To cast the film, the aqueous solution
was poured into a dry clean Teflon plate and then kept
in hot air oven at 60 �C for the first 30 min and then
the temperature was decreased to 40 �C for the next 24 h
(El-Setouhy & El-Malak, 2010). After complete drying, the
films were peeled off carefully from the Teflon plates,
wrapped in aluminum foil, and stored in airtight containers
at room temperature until further investigations.
Physicochemical evaluation of OL fast dissolving films
Physical appearance and weight variation
The appearances of the prepared films were evaluated by
visual observation of transparency or opaqueness. Weight
variation test was carried out by individually weighing 10
films of each formula then calculating the average compared
with other formulations. The thickness of the film was
measured using Vernier caliper micrometer (Shanghai
Measuring and Cutting Tools Limited Company, Shanghai,
China). The thickness was measured at five different locations
(four corners and one at center) and the average was recorded.
Surface pH determination
A combined pH electrode was used for testing the surface pH
of the film. The prepared film (4 cm2) was immersed in 2 mL
distilled water at room temperature. The pH was measured by
bringing the electrode in contact with the surface of the oral
film (Kunte & Tandale, 2010). The experiments were
performed in triplicate and the average was recorded.
Tensile strength
Tensile strength was determined using an apparatus fabricated
in laboratory. Increased stress was applied to the point at which
the strip specimen breaks (Felton et al., 2008). The prepared
film strips with dimensions of 1 � 3 cm2 were fixed from both
ends between two clamps. During measurement (n¼ 5), the
strips were pulled at the top clamp by adding weights in pan till
the film broke. The tensile strength represented by the weight
in grams required to break the film was determined using the
following equation (Yoon et al., 2012):
TS ¼ F=A ð1Þ
Table 2. Different formulation variables included into OL thin film.
RecordPolymer
type
Polymerconcentration
(mg)Plasticizer
type
Plasticizerconcentration
(mg)
1 HPMC (E5) 100.00 PG 10.002 HPMC (E5) 100.00 PEG400 10.003 HPMC (E5) 100.00 Glycerin 10.004 HPMC (E5) 100.00 PG 20.005 HPMC (E5) 100.00 PEG400 20.006 HPMC (E5) 100.00 Glycerin 20.007 HPMC (E5) 200.00 PG 20.008 HPMC (E5) 200.00 PEG400 20.009 HPMC (E5) 200.00 Glycerin 20.00
10 HPMC (E5) 200.00 PG 40.0011 HPMC (E5) 200.00 PEG400 40.0012 HPMC (E5) 200.00 Glycerin 40.0013 NaCMC 100.00 PG 10.0014 NaCMC 100.00 PEG400 10.0015 NaCMC 100.00 Glycerin 10.0016 NaCMC 100.00 PG 20.0017 NaCMC 100.00 PEG400 20.0018 NaCMC 100.00 Glycerin 20.0019 NaCMC 200.00 PG 20.0020 NaCMC 200.00 PEG400 20.0021 NaCMC 200.00 Glycerin 20.0022 NaCMC 200.00 PG 40.0023 NaCMC 200.00 PEG400 40.0024 NaCMC 200.00 Glycerin 40.00
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where F is the maximum load applied on the film in Newtons
(N) and A is the original cross-sectional area measured in
squared centimeter (cm2).
Folding endurance
This test was measured manually (n¼ 3) for the prepared FDF
formulae, where the prepared film (4 cm2) was folded
repeatedly at the same place for several times till visible
cracks were developed. The folding endurance is expressed as
the number of folds (number of times the film is folded at the
same place) required to break the film or to develop visible
cracks. This test was applied to check the ability of the sample
to withstand folding and also it gives an estimation of film
brittleness (Mishra & Gilhotra, 2008).
Drug content determination
Ten film pieces were used in this test, where 4 cm2 was cut
and dissolved in stoppered flask containing 100 mL of 20 mM
phosphate buffer pH 6.8. The contents were sonicated until
complete dissolution of the film. One mL of the solution was
filtered through Millipore filter (0.45 mm pore size) then
introduced into 25 mL volumetric flask and completed to
volume by the buffer solution. The absorbance of the solution
was measured using UV–visible spectrophotometer at lmax of
273 nm.
In vitro disintegration and dissolution studies
The disintegration test was carried out using disintegration
apparatus (Erweka, Milford, CT), where each one of the
six films was placed in the tubes of the container and
the cover disks were placed over it (Dahiya et al., 2009).
The disintegration test of the film was carried out according
to specifications of fast dissolving tablets reported in the
United State Pharmacopeia (USP). To mimic the mouth
saliva, 10 mM phosphate buffer pH 5.8 (900 mL) at
37 �C ± 0.5 �C was used as a disintegration medium and the
time taken for complete disappearance of the film was
measured in seconds.
The in vitro dissolution of OL from the investigated films
(cut into 4 cm2 pieces equivalent to 5 mg OL) was tested by
using USP dissolution tester, apparatus II (Hanson Research,
Chatsworth, CA). The paddles were rotated at 50 rpm in
900 mL of 10 mM phosphate buffer pH 5.8 with a temperature
of water bath kept at 37 ± 0.5 �C. Aliquots of 5 mL were
withdrawn from the dissolution medium at pre-determined
time intervals (1, 3, 5, 7, 10, 15, 20, 25, and 30 min) and then
replaced with fresh medium. The samples were filtered
through Millipore� filter (0.45mm) and OL content was
determined using UV spectrophotometer at lmax 273 nm using
simulated salivary fluid (SSF) as blank. The dissolution
profiles were plotted using average % OL released (n¼ 3)
from FDF and crystalline OL.
Modeling and optimization of OFDF preparation
The data set of OL FDF composed of 24 records (Table 3)
based on different formulation variables was subjected to the
modeling and optimization process. The inputs included
polymer type, polymer concentration, plasticizer type, and
concentration. The polymer types were coded with numerical
values as follows: HPMC E5 (1) and NaCMC (2) while the
plasticizer types were encoded as 3 for PG, 4 for PEG400, and
5 for Glycerol. The measured dependent variables included
tensile strength (N/cm2), disintegration time (s), folding
endurance, and percentage drug released after 10 min.
Modeling and optimization of the data were carried out
Table 3. Input and output film formulation variables used in the modeling and optimization process.
Input variables Output properties
RecordPolymer
typepolymer conc
(mg)Plasticizer
typePlasticizerconc (mg)
Tensile str.(N/cm2)
Folding end.(times)
Disintegrationtime (s)
% released(10 min)
1 1 100.00 3 10.00 4.73 109.00 15.00 97.542 1 100.00 4 10.00 4.05 138.00 9.00 98.133 1 100.00 5 10.00 4.35 157.00 23.00 96.134 1 100.00 3 20.00 4.65 95.00 11.00 99.795 1 100.00 4 20.00 3.89 132.00 4.00 100.236 1 100.00 5 20.00 4.22 146.00 17.00 99.317 1 200.00 3 20.00 7.08 148.00 21.00 90.488 1 200.00 4 20.00 6.12 189.00 14.00 95.449 1 200.00 5 20.00 6.95 207.00 27.00 90.05
10 1 200.00 3 40.00 6.43 135.00 18.00 92.7811 1 200.00 4 40.00 5.52 177.00 10.00 97.4312 1 200.00 5 40.00 6.03 195.00 22.00 91.2513 2 100.00 3 10.00 3.37 124.00 34.00 82.4514 2 100.00 4 10.00 2.76 181.00 28.00 85.2615 2 100.00 5 10.00 2.98 199.00 39.00 82.1916 2 100.00 3 20.00 3.24 119.00 26.00 87.9217 2 100.00 4 20.00 2.41 174.00 21.00 90.1618 2 100.00 5 20.00 2.91 188.00 33.00 86.4419 2 200.00 3 20.00 3.57 226.00 51.00 78.4320 2 200.00 4 20.00 3.11 265.00 44.00 80.9821 2 200.00 5 20.00 3.34 278.00 49.00 77.9522 2 200.00 3 40.00 3.36 213.00 46.00 83.9223 2 200.00 4 40.00 2.65 261.00 38.00 88.5224 2 200.00 5 40.00 3.04 270.00 43.00 81.49
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using artificial neural networks (ANNs)-Genetic algorithm
software package (INForm V3.71, Intelligensys Ltd., London,
UK) (Ali & Ali, 2013). The experimentally collected data set
was divided into training records (80%), testing records
(10%), and validation records (10%) for model training,
testing, and model validation, respectively. Predictability of
trained models was evaluated using the correlation coefficient
(R2) values computed automatically during training, testing,
and validation steps (Equation (2)). High R2 values closer to
unity indicate appropriate predictability of the trained model
(Plumb et al., 2002):
R2 ¼ 1�Pn
i�1 ðyi � y�i Þ2
Pni�1 ðyi � y�i Þ
2� 100 ð2Þ
where yi is the individual value of the dependent variable, yi is
the predicted value from the model, and yi- is the mean of the
dependent variable. In this formula, the numerator represents
the sum of squares for the error term (SSE) and the
denominator represents the total sum of variable is accounted
for in the model. The artificial neural network structure I(4)–
HL(3)–O(1) was used for model training (linking inputs and
the out-put properties), with four nodes representing the input
layer, three nodes in the hidden layer, and one node in the
output layer. Trusted models should result in validation
correlation R2 as high as those obtained during model training
and testing. The root mean-squared errors (RMSE) were also
calculated and compared with those of training and testing
(Ali & Abdelrahim, 2014).
After developing of the predictive models for each
property of the film, optimization was carried out by setting
the desired range for each of the out-put properties into the
model optimization screen and the desirability function was
selected as ‘‘tent’’ in the model optimization window (Plumb
et al., 2005). The desired minimum and maximum values for
the out-put properties were assigned as follows: tensile
strength (4–5 N/cm2), disintegration time (20–30 s), and
percentage dissolved in 10 min (95–100%). The model
generated solution represented a suggested optimized formula
for the FDF which was then prepared, characterized, and the
experimentally obtained properties were compared to those
previously predicted by the model.
Accelerated stability testing
The optimized FDF formula obtained by the model was chosen
for testing the physicochemical stability. First, the film was
wrapped in butter paper as one layer and above which a second
layer of aluminum foil was tightly applied. Samples of the
optimized films were stored at 40 �C/75% RH for a period of
12 weeks (Akil et al., 2011; Farid et al., 2015). Periodically,
samples were withdrawn at different predetermined time
intervals (0, 1, 2, 4, 6, 9, and 12 weeks) and examined
physically for any changes in color, appearance thickness, and
surface pH as well as chemically for their drug content.
In vivo evaluation of OL film in human volunteers
This study was carried out to compare the pharmacokinetics
of OL from the optimized fast dissolving film formulation
(FDF) to the reference products: A (Olazine oral tablets,
EIPICO, Cairo, Egypt) and product B (fast dissolving tablet
Zyprexa� Velotab, Lilly, Indianapolis, IN). A single oral
dose equivalent to 10 mg OL was given to the volunteers
using randomized crossover design in three phases with 1
week washout period between phases. Nine healthy man
volunteers aged between 23 and 34 years (median weight:
75 kg and median height: 183 cm) were chosen and divided
into three groups each containing three volunteers. Health
status of the volunteers was confirmed by complete medical
history, physical examination, and laboratory analysis for
complete hematological and biochemical examination. The
subjects were instructed to take no other drugs for 1 week
prior to and during the course of study. No consumption of
nicotine was permitted 12 h before and 24 h after drug
intake. Moreover, on each test day, coffee, tea, and cola
beverages were withheld from subjects 12 h before the
administration and till the blood sampling was completed.
The protocol of the study was conducted according to
Helsinky agreement protocol for human subjects and
according to the requirements of the ethical committee of
faculty of medicine, Assuit University, Assiut, Egypt. The
OFDF and the references were administered orally to the
volunteers after fasting overnight. Venous blood samples
(5 mL) were collected into heparinized tubes at certain time
intervals (0, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h). Plasma was
obtained by centrifugation at 3000 rpm (centrifuge R32,
Bombay, India) for 10 min and then samples were stored at
�20 �C until the time of analysis.
Chromatographic conditions
Plasma samples were analyzed using a sensitive, reprodu-
cible, and accurate LC-MS/MS method, developed, and
validated before the study. The isocratic mobile phase
consisted of methanol and 0.1% formic acid pH 4.3 (90:10
v/v), which was delivered at a flow rate of 0.2 mL/min into
the mass spectrometer’s electrospray ionization chamber.
Quantitation was achieved by LC-MS/MS detection in
positive ion mode for both OL and atorvastatin using a QT
mass detector (Matuszewski et al., 1998). The ion spray
voltage was set at 3500 V. The common parameters: nebulizer
N2 gas temperature: 350 �C, drying N2 gas flow: 200 ml/min,
sheath gas pressure: 30 Arb, and auxiliary gas pressure: 5 Arb.
The peak area of transition from the m/z 313.17 precursor ion
to m/z 256.13, with an collision energy of 30 eV for OL and
the m/z 559.39 precursor ion to m/z 440.27, with an collision
energy of 20 eV for atorvastatin.
A calibration curve of OL in plasma was conducted in
concentrations ranged from 0.1 to 30 ng/ml. A solvent
extraction procedure was used. Human plasma samples
(500 mL) and 50 mL of internal standard solution were placed
in 10 mL glass tubes then vortexed for 15 s. Five mL methyl-
ter-butyl ether was added and samples were then vortexed for
1 min. The tubes were then centrifuged for 5 min at 4000 rpm.
The upper organic phases were then transferred to clean glass
tubes and evaporated to dryness at 45 �C. Dry residues were
dissolved in 150mL of mobile phase and vortexed for 1 min to
reconstitute residues, and 10 mL were injected using the
autosampler.
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Pharmacokinetic analysis
Pharmacokinetic parameters were calculated from plasma
data using WinNonlin� (version 1.5, Scientific consulting,
Inc., Cary, NC). Non-compartmental analysis was adopted for
the calculation of the observed maximal drug concentration
Cmax (ng/mL) and the time needed to reach this concentration
tmax (h). The relative bioavailability was calculated from the
24 h area-under-the-plasma concentration versus time curve as
shown in the following equation:
Rel:Bioavailability ¼ AUCtest=AUCstandardð Þ�100 ð3Þ
Statistical analysis of the data was undertaken using
analysis of variance (ANOVA) test performed for the
untransformed data for the pharmacokinetic parameters
Cmax, tmax, AUC0–24, and t1/2 using the software SPSS 11.0
(SPSS Inc., Chicago, IL). The significance level was set at
p value¼ 0.05.
Result and discussion
Characterization of the co-amorphous dispersions
Saturated solubility
All the tested COAD samples showed increased OL water
solubility over the crystalline form (Table 4). The maximum
solubility (602-folds) was observed with ascorbic acid at a
molar ratio 1:2 (COAD2), so it was selected for performing
further solid state analysis and formulation of the oral fast
dissolving film.
Scanning electron microscopy
The results of SEM (Figure 1) indicated that large difference
in size and shape existed between the crystalline OL and the
ascorbic acid with smaller OL and larger cubic crystals of
ascorbic acid (Figure 1A and B). The co-amorphous disper-
sions COAD1 and COAD2 demonstrated the characteristic
amorphous aggregates and absence of the defined shape of
crystals (Figure 1C and D) The OFDF prepared from both
dispersions showed almost clear, transparent glassy, and
homogenous layer with completely dissolved OL into the
polymer matrix (Figure 1E and F).
Differential scanning calorimetry
DSC thermograms of the drug, ascorbic acid, physical
mixture, and solid dispersion systems are shown in Figure
2. The thermogram of OL showed a highly crystalline
component with a sharp endothermic peak at 194.01 �C(DH¼ 126.83 J/g) corresponding to its melting point. The
thermogram of ascorbic acid also showed a melting endo-
thermic peak at 191.24 �C. Physical mixtures showed broad
endotherm without sharp melting indicating interactions and/
or miscibility of the two components. Thermograms of the
dispersions containing OL–ascorbic acid in molar ratios; 1:1
(COAD1)and 1:2 (COAD2), showed broad peaks with
complete disappearance of the characteristic melting endo-
therms of parent components.
Fourier transform infra-red analysis
The FTIR spectra of OL, ascorbic acid, physical mixture
(1:1), and solid dispersions are presented in Figure 3. Pure OL
showed characteristic absorption bands at 3217 cm�1 (NH
stretching), 2929, 2836, and 2791 cm�1 (C–H stretching),
1586 cm�1 (C¼C stretching), 1461 cm�1 (C¼N stretching),
and 1283 cm�1 C–N stretching.(Ayala et al., 2006; Hiriyanna
et al., 2008) The FTIR spectra of ascorbic acid indicated a
characteristic peak at 1754 cm�1 which is attributed to the
C¼O stretching vibration commonly observed for carboxyl
groups (Zhang et al., 2015). The characteristic peaks of pure
OL and ascorbic acid were found to be present in the spectra
of the physical mixture; however, they were shorter than
original components. The prepared solid dispersion formula-
tions (COAD1 and COAD2) showed shortening, broadening,
and shifting of certain peaks of OL.
X-ray diffraction
The diffraction spectrum of pure OL (Figure 4) showed highly
crystalline component as demonstrated by the characteristic
intense peaks at 2� 8.67, 17.09, 19.87, 21.05, 21.54, and
23.95� which were identical to those reported in the literature
(Tiwari et al., 2007). The XRD pattern for ascorbic acid also
showed multiple sharp characteristic diffraction lines at 2�10.63, 15.89, 17.59, 25.33, 27.25, 28.19, 30.18, and 34.85�
indicating a purely crystalline compound. The XRD spectra of
the drug–ascorbic acid 1:1 physical mixture showed less
intense spectrum compared with the parent components. The
diffraction lines of the expected COADs demonstrated the
disappearance of the characteristic peaks of both OL and
ascorbic acid.
Physicochemical evaluation of the prepared films
The prepared films were elegant, transparent, and flexible
with smooth surface and showed no blooming. The measured
average thickness of the films was 0.18 ± 0.02 mm. The
surface pH of all prepared films was 5.90–6.90 which is in the
range of salivary pH, hence no expected sensation of irritation
to the oral cavity was found. The drug content values were in
the range of 96.79–99.37% for the different formulations with
standard deviation less than 2% indicating that the drug was
uniformly dispersed throughout the film. The TS of the films
was found to be in the ranged 2.41–7.08 N/cm2, which is
considered adequate TS for handling and certain flexibility to
guarantee patient compliance (Lim & Hoag, 2013). The
results of folding endurance were found to be between 95 and
278 times, which could be considered relatively variable due
Table 4. Saturated solubility of co-amorphous dispersions compared topure OL.
Type offormulation
Conformeracid
Molarratio
Saturatedsolubility(mg/mL)
Numberof folds
increase insolubility
Percentageincrease insolubility
Olanzapine – – 0.0334 ± 0.015 – –F1 Ascorbic 1:1 6.303 ± 0.38 191 530F2 Ascorbic 1:2 19.855 ± 0.52 602 1886F3 Citric 1:1 4.293 ± 0.23 130 329F4 Citric 1:2 15.742 ± 0.42 477 1474F5 Tartaric 1:1 2.837 ± 0.11 86 184F6 Tartaric 1:2 12.489 ± 0.44 378 1149
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Figure 1. Scanning electron micrographs of pure olanzapine (A), its physical mixture with ascorbic acid (B), co-amorphous dispersion 1:1 (C),co-amorphous dispersion 1:2 (D), 1:1 film (E), and 1:2 film (F).
Figure 3. IR spectra for olanzapine (OL), ascorbic acid (AS), their 1:1physical mixture (PM), and co-amorphous dispersions COAD1 (1:1) andCOAD2 (1:2).
Figure 2. DSC thermograms for olanzapine (OL), ascorbic acid (As),(1:1) physical mixture (PM), and co-amorphous dispersions COAD 1(1:1) and COAD 2 (1:2).
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to subject hand errors. The folding endurance was directly
proportional to concentration of polymer and inversely to
plasticizer concentration.
Assessment of in vitro disintegration and dissolutionof the film
The disintegration time of the films was in the ranged of
4.00–51.00 s which is less than 1 min and considered accept-
able time as reported in previous studies (Liew et al., 2012).
It was clear that the time was increased as the polymer
concentration increased. The in vitro dissolution profiles of
OL from the optimized film in SSF (pH¼ 5.8) compared with
OL powder are shown in Figure 5. The optimized fast
dissolving film achieved almost complete dissolution within
10 min compared with only 55.34% dissolved for those
containing crystalline drug (30 min) which were also com-
patible with fast dissolving films reported in the literature
(Vila et al., 2014). These results indicated that the COAD
used to prepare the films greatly enhanced the extent and rate
of dissolution of OL from the prepared OFDF. This
enhancement was a result of the synchronized dissolution of
OL and ascorbic acid brought about by the co-amorphous
dispersion (Lobmann et al., 2011). The cumulative percentage
of drug released after 10 min (Q10min) was evaluated among
different films. The drug dissolution from all formulae
decreased as the concentration of the polymer increased,
this expected result was in agreement with the data reported in
the literature for fast dissolving oral films (Scott et al., 2013).
Modeling of film formulation
The relationships between film formulation variables and
each of the output properties could be explained from the
response surface plots shown in Figure 6. The results of the
modeling experiment indicated a highly trusted predictive
model as confirmed by high training correlation R2 (92–
99%), testing R2 (78–94%), and validation R2 (87–89.90%).
The model trustability is also confirmed by the low values
of the RMSE of training, testing, and validation data sets
(Tables 5 and 6). The effects of polymer type and
concentration on the film disintegration time demonstrated
that polymer 1 (HPMC E15) resulted in lower disintegration
time than polymer 2 (NaCMC). The time was also increased
at higher concentration of polymers (200 mg) as shown in
Figure 6(A). The plasticizer type 4 (PEG 400) showed
lowest values of disintegration time of the film compared
with PG (type 3) and glycerin (type 5) and the time linearly
decreased with increased plasticizer concentration (Figure
6B). For tensile strength, both polymer type and concentra-
tion were found to directly increase film tensile strength
(Figure 6C). As previously noted with disintegration time,
the tensile strength of the film had its lowest values with
plasticizer 4 (PEG 400) as demonstrated by the large
curvature of Figure 6(D). It was also noticed that PG showed
somewhat higher tensile strength than glycerin and the
increased concentration of any of the plasticizers led to a
direct decrease in film strength. On one hand, for, percent-
age OL released from the film, the relationship observed
with polymer type indicated that HPMC E5 (type 1) resulted
in higher % drug release than type 2 (NaCMC) as illustrated
in Figure 6(E). This could be due to the formation of
stronger matrix layer with higher tortuosity and poor water
porosity for diffusion of drug caused by more intimate
contact between particles of HPMC at high concentration
(Sapkal et al., 2011). Moreover, higher polymer concentra-
tion resulted in viscous environment of the system retarding
water movement into the matrix and diffusion of the drug
into the surroundings (Dunn & English, 2002). On the other
hand, NaCMC has higher molecular weight than HPMC E5
which supports the formation of stronger matrix and lower
release rates (Table 7).
The type of plasticizer showed a slow increase in % drug
released moving from plasticizer 3-4-5 (PG-PEG400-Gly) and
the increased concentration of the three polymers led to a
direct increase in % OL released up to a plasticizer
concentration of 20–22% followed by a slow decrease
possibly due to increased viscosity of the film matrix
(Figure 6F). Folding endurance unfortunately did not result
in a good model during preliminary model training most
probably due to high variability and scatter of its values and
hence was excluded from the final model.
Figure 4. X-ray diffraction lines of olanzapine (OL), ascorbic acid (AS),1:1 physical mixture (PM), 1:1 co-amorphous dispersion (COAD1), and1:2 co-amorphous dispersion (COAD2).
Figure 5. Dissolution profiles of pure olanzapine (OL) compared withthe optimized fast dissolving film (OFDF).
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Model optimization
The model-generated optimized formulation for OL film was
composed of HPMC E5 or polymer 1 (178.01 mg) and PEG
400 or plasticizer type 4 (40 mg) as demonstrated in Table 7.
The desirability of the obtained model exceeded 99% which
represents high closeness of the obtained model predictions
from the desired values entered during optimization. The
experimental testing of the optimized formulation indicated
similar properties to those predicted by the model. The actual
tensile strength was found to be 4.93 N/cm2, the disintegration
time was 8.52 (s), and the percentage OL released was
97.47(%), respectively. The difference between the actual and
the model predicted properties was found to be statistically
insignificant (p50.05) which ensured model trustability.
Accelerated stability studies
Fast dissolving films were found to be physically and
chemically stable at the selected temperature and humidity
(40 �C/75%RH) with no significant change in terms of
physical characteristics and drug content (98.33%). The
percentage OL remaining up to the end of the storage
period (3 months) at the above-mentioned storage conditions
was found to be within the USP-permitted values (90–110%)
of the original content in the film (5 mg/4 cm2).
Figure 6. 3D response surface plots showing effects of different input variables on film disintegration time (A and B), tensile strength (C and D), and %OL released (E and F).
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In vivo evaluation of the film
The mean plasma concentration–time curves of OL following
oral administration of the optimized formula (OFDF), the oral
generic product A, and the fast dissolving Product B tablets are
shown in Figure 7. Higher mean Cmax were obtained from the
OFDF followed by product B and product A tablets. However,
the differences between the three treatments for Cmax were
found to be statistically insignificant (p50.05). The mean
AUC0–24 h which reflects the total amount of drug absorbed
over the 24 h time period was significantly higher for the fast
dissolving film under test compared with the two reference
formulations (Table 8). Shorter tmax was observed with the
film followed by the references B and A tablets.
Table 5. Model training and testing ANOVA statistics for OL fast dissolving film output properties.
Output property Source of variation Sum of squares Degrees of freedom Mean squares RMSE Computed f ratio
Tensile strength (N/cm2) Model 43.4954 19 2.28923 1.513 28.8634Error 0.0793126 1 0.07931 0.282Total 43.6201 20
Covariance term Sum of errors0.0453962 0.0014496
Train Set R2 99.82%Test Set R2 94.69%
Disintegration time (s) Model 3955.37 19 208.177 14.428 10.0595Error 20.6946 1 20.6946 4.549Total 3977.24 20
Covariance term Sum of errors1.17717 0.0488199
Train set R2 99.48%Test set R2 91.40%
% Released (10 min) Model 979.519 19 51.5537 7.180 0.672918Error 76.6121 1 76.6121 8.753Total 1054.28 20
Covariance term Sum of errors1.85219 0.308051
Train Set R2 92.73%Test Set R2 78.65%
Table 6. Model validation ANOVA statistics for each output property.
Output property Source of variation Sum of squares Degrees of freedom Mean squares RMSE Computed f ratio
Tensile strength (N/cm2) Model 5.7283 19 0.30149 0.549 11.81Error 0.43385 17 0.02552 0.160Total 3.8653 2
Covariance term Sum of errors2.29694 0.51135
Validation R2 88.78%Disintegration time (s) Model 353.2 19 18.5895 4.312 6.79
Error 46.517 17 2.7363 1.654Total 368.452 2
Covariance term Sum of errors31.2657 7.8533
Validation R2 87.37%% Released (10 min) Model 83.5956 19 4.3997 2.098 4.81
Error 15.5611 17 0.9154 0.957Total 140.236 2
Covariance term Sum of errors41.0797 0.4412
Validation R2 88.90%
Table 7. Model optimized solution for desirable film properties.
X1 X2 X3 X4 Y1 Y2 Y3
Optimizedsolution Desirability
Polymertype
polymerconcentration (mg)
Plasticizertype
Plasticizerconcentration (mg)
Tensilestrength (N/cm2)
Disintegrationtime (s)
% released(10 min)
Model generated 0.99 1.00 178.01 4.00 40.00 5.00 8.06 95.04Experimental – 1.00 178.01 4.00 40.00 4.93 8.52 97.47
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Discussion
The use of ascorbic acid in the preparation solid dispersions
and successful OL COAD systems was found to be useful in
enhancing water solubility of OL by more than 600-folds
which led to high dissolution and expected maximized
absorption. This approach is considered a highly effective
method usually used for the formation of cocrystals to
improve solubility of poorly soluble drugs (McNamara et al.,
2006). However, in this study, a co-amorphous dispersion was
obtained at molar ratios of OL:ascorbic acid; 1:2 and 1:3
using rapid solvent evaporation under vacuum. The inter-
action between ascorbic acid and OL was effected most
probably by H-bonding of the NH group of OL and the
carbonyl group of ascorbic acid (Forster et al., 2001). In
addition to its solubility enhancing effect in the prepared
dispersions, ascorbic acid also is expected to provide
antioxidant and neuroprotective effects to the final film
formulation (Allahtavakoli et al., 2015; Xu et al., 2015).
The DSC results above confirmed the formation of
homogenous single phases between OL and ascorbic acid
through complete amorphization and absence of true melting
endotherms. This complete miscibility between the two
components at 1:1 and 1:2 molar ratios as indicated by the
broad DSC thermograms of the dispersions (Figure 2) may
suggest the formation of homogenous co-amorphous disper-
sions (Ali et al., 2015; Jensen et al., 2015).
From the IR data, it becomes obvious also that interactions
between functional groups of OL and As acid have taken
place. For example, the C–H stretching and C¼N stretching
were shortened and broadened and the shallow peak of N–H
stretching also demonstrated shifting to 3394 cm�1 instead of
3217 cm�1 (Figure 3). These results strongly suggest that the
interaction between OL and ascorbic acid may have taken
place through H-bonding (Mistry et al., 2015).
The XRD results (Figure 4) also confirm the interactions
and formation of single homogenous phase by the appearance
of the amorphous halo characteristic of single co-amorphous
dispersions (Lobmann et al., 2013; Dengale et al., 2014).
The incorporation of OL–ascorbic acid co-amorphous
dispersions in fast dissolving oral film was intended to
provide a simple easily administered dosage form for the
application inside the mouth. The formulated film was found
to have acceptable transparent appearance and mechanical
properties, disintegration, and dissolution. Almost complete
dissolution from the film was attained within 10 min. Also,
the drug was found to be stable in the film for up to 12 weeks
at 40 �C and 75% RH which could be attributed to compati-
bility between polymers used in the film (PEG 400 and
HPMC E5) and the COAD system. This increased phase
stability possibly occurred through extending the supersatur-
ation state (Kawakami, 2012).
From the above response surface plots, it could be
concluded that HPMC E5 as the film forming polymer and
PEG 400 as the plasticizer had the major effects on optimum
film properties (tensile strength, disintegration time, and %
OL released). Therefore, the model optimization resulted in a
suggested formula with maximum dissolution and fast
disintegration containing the above-mentioned polymers.
This formula when tested for the actual properties was
found to have the required disintegration, dissolution, and
mechanical strength as those predicted by the model. The
comparative pharmacokinetic evaluation of the film proved
that formulation of OL in the form of OFDF using the co-
amorphous phase was a successful strategy for enhancing the
pharmacokinetic parameters. The higher Cmax, short tmax, and
the improved bioavailability observed for OFDF relative to
the commercially available formulations could be attributed to
the rapid disintegration and dissolution of OL in saliva
brought about by the COAD system incorporated into the
optimized film leading to fast absorption.
Figure 7. Plasma concentration versus timecurves of olanzapine following oral adminis-tration of Olazine tablets (product A),Zyprexa� velotab (product B), and fastdissolving film (OFDF) to human volunteers.
Table 8. Comparative pharmacokinetics following oral administration ofOL film and reference formulations (products A and B) to humanvolunteers.
Formula
Parameter Product A Product B OF FDF
Cmax (ng/ml) 10.85 ± 1.29 12.96 ± 2.64 14.22 ± 2.95tmax (h) 5.50 ± 1.00 3.75 ± 0.50 2.75 ± 0.50t½ el (h) 8.29 ± 0.84 7.67 ± 0.96 7.74 ± 1.44AUC(0–24) (ng h/ml) 113.61 ± 24.82 125.34 ± 34.18 144.44 ± 43.01R. bioavailability 90.64% 100% 115.83%
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Conclusion
The physicochemical properties of OL were highly improved
using the principle of solid dispersion amorphization with a
highly soluble coformer such as ascorbic acid. The results of
solid state characterization of OL COADs indicated the
formation of single homogenous phase through H-bonding
interactions. This homogenous dispersion was further stabi-
lized through incorporation with selected polymers to form a
fast dissolving oral film. The optimized fast dissolving films
were successful formulations which provided highly dissol-
ving OL in a simple and easily administered dosage form for
psychotic patients. The pharmacokinetics data indicated that
the OFDF ensured improved bioavailability of OL compared
with the marketed reference products. This can be attributed
to faster dissolution leading to rapid absorption of OL from
the buccal mucosa which undoubtedly resulted in a decreased
pre-systemic biotransformation and maximized the
bioavailability.
Acknowledgements
The authors of this manuscript acknowledge the help given by
the technicians working at the central laboratory of Beni Suef
University for help and support during use of the LC-MS and
SEM equipment. Also, a special acknowledgment is directed
to all members of the human research ethical committee at
Faculty of medicine, Assiut University, Egypt. The human in
vivo study performed in this research paper was undertaken
according to the guidelines outlined in the Helsinki agreement
for human research.
Declaration of interest
The authors report that they have no conflicts of interest
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DOI: 10.3109/10717544.2016.1153746 Evaluation of an optimized fast dissolving oral film 13
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