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Development, optimization and in vivo characterization of domperidone-

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DOI: 10.3109/03639045.2015.1104346

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 Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: http://www.tandfonline.com/loi/iddi20

Development, optimization and in vivo

characterization of domperidone-controlled
release hot-melt-extruded films for buccal delivery

Chinna Reddy Palem, Narendar Reddy Dudhipala, Sunil Kumar Battu,

Michael A. Repka & Madhusudan Rao Yamsani

To cite this article: Chinna Reddy Palem, Narendar Reddy Dudhipala, Sunil Kumar Battu,
Michael A. Repka & Madhusudan Rao Yamsani (2015): Development, optimization and in
vivo characterization of domperidone-controlled release hot-melt-extruded films for buccal
delivery, Drug Development and Industrial Pharmacy, DOI: 10.3109/03639045.2015.1104346

To link to this article: http://dx.doi.org/10.3109/03639045.2015.1104346

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ISSN: 0363-9045 (print), 1520-5762 (electronic)

Drug Dev Ind Pharm, Early Online: 1–12

! 2015 Taylor & Francis. DOI: 10.3109/03639045.2015.1104346

RESEARCH ARTICLE

Development, optimization and in vivo characterization of

domperidone-controlled release hot-melt-extruded films for
buccal delivery
Chinna Reddy Palem1, Narendar Reddy Dudhipala1, Sunil Kumar Battu2, Michael A. Repka2, and Madhusudan Rao
Yamsani1
1
National Facilities in Engineering and Technology with Industrial Collaboration (NAFETIC) Centre, University College of Pharmaceutical Sciences,
Downloaded by [narendar Dudhipala] at 11:46 07 November 2015

Kakatiya University, Warangal, Telangana, India and 2Department of Pharmaceutics, School of Pharmacy, the University of Mississippi,
University, MS, USA

Abstract Keywords
Objective: The aim of the present investigation was the development and in vivo character- Bioadhesion, central composite design, con-
ization of domperidone (DOM) hot-melt extruded (HME) controlled release films by central trolled release, domperidone, EVIV correl-
composite design (CCD) for buccal delivery. ation, ex vivo permeation, hot-melt
Methods: Concentration of PEO N750 (X1) and HPMC E5 LV (X2) as independent variables and extrusion, in vitro dissolution
tensile strength (Y1), percent drug release at 6 h (Q6, Y2) and percent drug permeated at 6 h (Y3,
P6) as responses. In total, 13 formulations were prepared and studied. HME films were evaluated History
for drug excipient compatibility, physico-mechanical properties, drug content, in vitro drug
release, bioadhesion, swelling and erosion, ex vivo permeation. Furthermore, statistically Received 3 August 2015
optimized formulation was subjected for bioavailability studies in healthy human volunteers. Revised 17 September 2015
Results: Statistically optimized formulation exhibited a tensile strength (3.86 kg/mm2), Accepted 2 October 2015
93.62 ± 2.84% of drug release and 63.36 ± 2.12% of drug permeated in 6 h. HME films Published online 4 November 2015
demonstrated no drug excipient interaction and excellent content uniformity. Furthermore,
optimized formulation exhibited elongation at break (38.6% mm2), peak detachment force
(1.75 N), work of adhesion (3.21 mJ), swelling index (240.4%) and erosion (8.5%). Bioavailability
from the statistically optimized buccal films was 3.2 times higher than the oral dosage form
(p50.05). The ex vivo–in vivo correlation was found to have biphasic pattern and followed type
A correlation. The stability of the optimized formulation was studied and no significant changes
were detected in 6 months.
Conclusion: The results indicate that hot-melt extrusion is a viable technique for the preparation
of DOM buccal-adhesive controlled release films with improved bioavailability by CCD.

Introduction Hot-melt extrusion technology is a thermal processing tech-

nique initially introduced in the plastics industry. In addition,
Domperidone (DOM) is a poorly water-soluble dopamine (D2)
poorly compactable materials can be prepared as tablets without
receptor antagonist, widely used in the treatment of motion
a compression process by cutting an extruded rod to the
sickness. In humans, peak plasma levels of DOM occur within
desired dimensions3. However, over the past couple of decades,
10–30 min following intra-muscular injection and 30 min after
its focus has been on numerous applications in the growing
oral (fasted) administration. It was reported to be rapidly absorbed
pharmaceutical field, which is evident from the published
after oral administration, but undergoes extensive first-pass
scientific literature4. During hot-melt extrusion of pharmaceutical
metabolism; leading to poor bioavailability of 15%1. In addition,
dosage forms, a complex mixture of active ingredient, thermo-
DOM is already very active at low dose, low molecular weight,
plastic polymeric carrier, and other processing aids, including
lipophilic in nature and is good permeability through porcine
plasticizers and antioxidants, is heated and softened inside the
buccal membrane2. All these parameters make this drug an
extruder and then pressurized through a die to form either
interesting candidate for buccal administration.
granules, pellets, tablets or films. However, a search of the
literature in the scientific field will yield relatively few articles
with hot-melt extrusion technology applied to pharmaceutical
Address for correspondence: Prof. Madhusudan Rao Yamsani, National systems. A few researchers have recently demonstrated that the
Facilities in Engineering and Technology with Industrial Collaboration HME technique is a viable method to prepare pellets5, sustained
Centre, University College of Pharmaceutical Sciences, Kakatiya
University, Warangal 506 009, Telangana, India. Tel: +91 8702438844.
release tablets6, targeted delivery, development of solid disper-
Fax: +91 8702453508. E-mail: ymrao123@yahoo.com, sions7,8 and novel delivery systems via extruded films9,10,11,12.
pcreddy147@yahoo.co.in HME technique is also applied for the production of medical
 2 C. R. Palem et al. Drug Dev Ind Pharm, Early Online: 1–12

devices and implants13, for drug carriers14 and stabilization of
products15, Indeed, very few oral transmucosal systems are
currently available in the market. Of these systems, there are none
produced by HME, and none that contain DOM. Many of the
available transdermal and/or transmucosal drug delivery systems
produced employ film-casting technique utilizing either organic
or aqueous solvents. Disadvantages accompanying with solvent
casting techniques includes long processing time, environmental
concerns (organic solvent disposal), and excessive costs11. On the
contrary, HME offers many advantages over these traditional
processing techniques, including the fact that no solvents being
utilized, and providing an environment friendly technology and
decreased production costs. Thus, an efficient, economical drug
delivery system for the transmucosal delivery is a very likely
outcome utilizing HME. In addition, development of a dosage
form that can remain in close contact with the buccal mucosa for a
sufficient period, to allow efficient diffusion of the therapeutic
agent from the dosage form into the systemic circulation, could be
a significant challenge to the therapeutic agents for their
transmucosal delivery. To improve the efficiency of trans-buccal
systems, we have made an attempt utilizing HME technique.
Downloaded by [narendar Dudhipala] at 11:46 07 November 2015
Currently, statistical optimization is gaining importance in the
formulation development. Response surface methodology (RSM)
is an experimental design in which the factors involved and their
relative importance can be assessed. RSM permits a deeper
understanding of a process or product and has important
applications like optimization and in establishing the robustness
of the product21. Central composite design (CCD) is a progression
from the factorial designs which have been widely used in RSM
and optimization22.
The aim of the present research work is to investigate the
feasibility of producing stable polyethylene oxide-based HME
controlled release films containing DOM for buccal delivery by
using CCD. These extruded formulations were also subjected to
wide-ranging in vitro characterization tests such as physico-
mechanical, bioadhesion, in vitro release, ex vivo permeation,
stability, in vivo bioavailability in healthy human male volunteers
and ex vivo–in vivo correlation of the data.
Methodology
Materials

The buccal administration of drugs is drawing considerable
attention since it has an excellent accessibility, an expanse of
smooth muscle, robustness of the epithelium, relatively immobile
mucosa and comparatively less susceptibility to enzymatic
activity, hence suitable for administration of retentive dosage
forms16. Direct access to systemic circulation through the internal
jugular vein bypasses drugs from the hepatic first-pass metabol-
ism leading to high bioavailability17.
Bioadhesive buccal films are innovative dosage forms with the
ability to adhere to the mucosal surface and subsequently hydrate
to release and deliver drugs across the buccal membrane18. These
are designed to overcomes drug degradation in the GI tract, active
drug loss due to first-pass metabolism, and inconvenience of
parenteral administration19,20.
Table 1. Independent variables and their levels used in the CCD.
Levels used, actual (coded)
Independent variables Low (1) Medium (0) High (+1)
X1: concentration of 40 80
PEO NP750 (%w/w)
X2: concentration of HPMC 20 40
E5 LV (%w/w)
Domperidone, HPMC E5 were gifted by Dr Reddys Laboratories
(Hyderabad, India). Poly(ethylene oxide) and vitamin E succinate
were purchased from Aldrich Chemical Company (Milwaukee,
WI). Polyester backing membrane was gifted by 3 M (St. Paul,
MI). Mucin (Crude Type II) was purchased from Sigma-Aldrich
(Hyderabad, India) and was used without further purification.
Phosphate buffer saline (PBS), Dulbecco’s and Phenol red were
purchased from Hi Media (Mumbai, India). All reagents used
were of analytical grade.
CCD – design of experiments
In this study, a CCD was used to optimize the formulation
variables of HME controlled release films of DOM for buccal
delivery containing three factors and evaluated at two levels. The
independent variables in our studies were concentration of PEO
N750 (X1), concentration of HPMC E5 (X2) and for each factor an
experimental range was selected (Table 1) based on the results of
preliminary experiments. The concentration of plasticizer was
kept constant at 20% w/w. The tensile strength (Y1), percentage
drug released at 6 h (Y2:Q6) and percentage drug permeated at 6 h
120
(Y3:P6) were included as responses. The experiments were
60 designed by using DOE software (Version 9.0.0.1, Stat-Ease
Inc., Minneapolis, MN) at all 13 possible combinations and the
layout of the design is shown in Table 2. The DOE software was
used to give information not only on the critical values required to

Table 2. Composition of DOM buccal films by CCD – variables and responses.

Weight Thickness Drug E/Ba

Run X1 X2 Y1 Y2 Y3 (mg) (mm) content (%) (% mm2)
CR1 80 25 4.16 80.76 55.23 102.1 830 98.2 33.3
CR2 80 15 4.01 83.54 57.88 101.3 825 98.6 33.1
CR3 40 15 2.15 105.4 70.54 97.2 785 97.1 35.3
CR4 60 20 3.9 99.73 67.24 102.4 790 99.6 42.1
CR5 60 20 3.88 99.43 66.99 102.3 790 99.5 42.2
CR6 60 20 3.83 99.76 66.94 102.3 790 99.6 42.1
CR7 60 12.92 3.21 90.33 58.88 101.1 780 99.1 40.3
CR8 88.28 20 4.12 79.44 49.65 102.2 830 98 32.9
CR9 60 27.07 3.68 93.22 60.32 102.1 790 99.1 40.5
CR10 60 20 3.86 99.82 67.13 102.4 790 99.4 42.1
CR11 31.71 20 1.98 108.5 79.34 99.6 780 97.8 34.4
CR12 40 25 2.21 103.4 73.21 100.1 780 98.2 36.4
CR13 60 20 3.88 99.77 66.97 102.3 790 99.5 42.2

Notes: X1, concentration of PEO N750 (% w/w); X2, concentration of HPMC E5 LV (% w/w). Responses Y1, tensile strength
(kg/mm2); Y2, Q6 drug released at 6 h (%) and Y3, P6 drug permeated at 6 h, (%); E/Ba, elongation at break.
 DOI: 10.3109/03639045.2015.1104346
achieve the desired response, but also the possible interactions of
the selected independent variables on the dependent variables.
Ex vivo domperidone permeation studies
Franz diffusion cell with a receptor compartment volume of
25 mL and porcine buccal mucosa was used for ex vivo
domperidone permeation study. Porcine buccal mucosa is similar
in permeability, barrier lipid composition, thickness, histology to
human buccal mucosa23 and is available in large quantities from
slaughterhouses. The isolated porcine buccal membrane was
carefully mounted between the two compartments of Franz
diffusion cell. PBS pH 7.4 containing 25% v/v of polyethylene
glycol (PEG 400) was placed in the receptor compartment. The
donor compartment contained DOM dissolved in a solution of
PBS pH 7.4 and PEG 400 (1:1). The donor compartment also
contained phenol red, a non-absorbable marker compound, at a
concentration of 20 mg mL1. The entire set-up was placed over
magnetic stirrer and the temperature was maintained at 37  C24,25.
Samples of 1 mL were collected at predetermined time intervals
from the receptor compartment and replaced with an equal
Downloaded by [narendar Dudhipala] at 11:46 07 November 2015
volume of fresh solution, and samples were analyzed using ultra
fast liquid chromatography (UFLC).
Estimation of drug content by UFLC
The UFLC system (Shimadzu, Kyoto, Japan) utilized for the
analysis consisted of two LC-20AD prominence liquid chroma-
tographic pumps, RF-10AXL, fluorescence detector, CTO-20AC
Prominence column oven with Lab solutions (LC solutions,
Shimadzu, Japan) software. The analytical column used was Onyx
monolithic C18 column (Phenomenex, 100 mm  4.6 mm i.d.,
particle size 5 mm) at 25  C temperature. The mobile phase used
was a mixture of 62:38 of 10 mM phosphate buffer pH adjusted to
3.1 with orthophosporic acid and methanol. The flow rate was
1 mL min1 and detection was carried out at excitation 282 nm
and emission 328 nm. A calibration curve is plotted for DOM in
the concentration range of 0.05–10 mg mL1. A linear relationship
was observed between the concentration of DOM and the peak
area of DOM with a correlation coefficient (r2 ¼ 0.999). The
required studies were carried out to estimate the precision and
accuracy of the UFLC method.
Preparation of controlled release hot-melt extruded DOM
films
Controlled release hot-melt extruded formulations were prepared
using either PEO N750 alone or its combination with HPMC E5
LV as a polymer matrices, and vitamin E succinate as a processing
aid as per Table 2. The pure polymers were oven-dried at 50  C
for 24 h to remove any moisture that had been previously adsorbed
prior to extrusion. All of the formulation ingredients other than
the active moiety were weighed, sifted through a 35 mesh, and
mixed uniformly. Drug and formulation mixtures were further
mixed in a Patterson Kelly twin-shell dry blender (The Patterson-
Kelly Co., Inc., East Stroudsburg, PA) at a speed of 25 rpm for
10 min to improve content uniformity of the drug in the final
product. Final blend for each of these formulations was hand-fed
at a near-constant flow through the mini-hopper and extruded at a
screw speed of 50 rpm with the barrel temperatures ranging from
120 to 160  C utilizing a bench top co-rotating twin-screw hot-
melt extruder (Prism 16 mm EuroLab, Thermo Electron
Corporation, Newington, NH) using a transverse-slit die. During
the extrusion, torque was maintained at 20–40% (10–13 N m) and
the die pressure for all of the formulations was monitored and
recorded. The produced HME films were cut to desired size,
flushed with nitrogen, packaged in aluminum foil and stored in
foil-lined polyethylene bags until further analysis.
Domperidone hot-melt extruded buccal films 3
In vitro drug release study
In vitro drug release studies were performed utilizing modified
dissolution test apparatus (Electrolab TDT-08L, Hyderabad,
India) United States Pharmacopeia (USP) XXXI apparatus 5,
paddle-over-disk method. The extruded films were cut into
patches of circular shape of 1.6 cm diameter, and covered with a
polyester backing membrane on one side of the film, including the
circumference, leaving the other side open. These films were
sandwiched between the watch glass and a mesh to keep the drug
release unidirectional. The release studies were performed on the
circular films utilizing 500 mL of 0.4% w/v sodium lauryl sulfate
in water as dissolution media at 37 ± 0.5  C, maintaining an
agitation speed of 25 rpm. Samples (5 mL) were collected at
predetermined time intervals, and replaced with an equal volume
of fresh dissolution medium and analyzed utilizing UFLC.
Statistical analysis of the data and validation of the model
In this study, evaluation of the quality of fit of the model was
performed employing DOE software (Version 8.0.7.1, Stat-Ease
Inc., Minneapolis, MN). Polynomial models including linear,
interaction and quadratic terms were generated for all the
response variables using multiple linear regression analysis. The
best fit model was selected based on comparison of several
statistical parameters, including the coefficient of determination
(R2), adjusted R2 and coefficient of variation (CV) provided by
DOE software. Furthermore, analysis of variance (ANOVA) was
used to identify significant effects of factors on response
regression coefficients. The F test and p values were also
calculated using the software. The relationship between the
dependent and independent variables was elucidated using
response surface plots (contour and 3D surface). These plots
were used to study the effect of various factors on the response at
a given time and to predict the responses of dependent variables at
intermediate levels of independent variables. Finally, a numerical
optimization technique (desirability approach) and a graphical
optimization technique (overlay plots) were used to generate new
formulation with desired responses. To validate the chosen
experimental design, the responses of experimental values were
quantitatively compared with responses of predicted values and
percentage relative error was calculated.
Thermal gravimetric analysis (TGA)
A TGA (Perkin Elmer, Pyris 1, Norwalk, CT) was employed to
investigate the thermal stability of DOM, PEO N750, HPMC E5
LV and vitamin E succinate.
The thermal stability of the drug, physical mixtures and
statistically optimized HME CR film samples was determined as a
function of weight loss using TGA. The analysis was performed
on the samples (2–3 mg) using a Perkin-Elmer Pyris 1 thermo-
gravimetrical analyzer operated at a ramp rate of 20  C/min from
a temperature of 30–160  C, held for 5 min at 160  C, and further
heated to 200  C at the same heating rate. The percentage weight
loss for all of the samples tested was recorded using Pyris 1 TGA
software. All TGA runs were performed in an open pan with
purge and protective nitrogen gas flow at 40 mL/min.
Scanning electron microscopy studies
HME polymeric matrices along with their respective physical
mixture and the pure polymer were evaluated for the physical
appearance of the drug-loaded polymeric particles utilizing a
scanning electron microscope (SEM). The samples were mounted
onto an aluminum stage using adhesive carbon tape. Samples
were then sputter coated with gold under an argon atmosphere
using a Hummer 6.2 Sputter Coater (Ladd Research Industries,
 4 C. R. Palem et al.
Williston, VT) in a high vacuum evaporator equipped with an
omni-rotary stage tray to produce uniformly coated irregular
specimens without thermal damage. The processed samples were
examined and the images were captured using a JEOL JSM-5600
scanning electron microscope (JEOL USA, Inc., Waterford, VA)
by operating at an accelerating voltage of 6–7 kV.
Differential scanning calorimetry analysis
Differential scanning calorimetry (DSC) analysis was carried out
utilizing a Perkin-Elmer Diamond DSC instrument to evaluate
any possible drug interaction with the employed excipients and
thermal characteristics of the individual additives used in the
formulation. Samples of 3–5 mg of pure drug and each of the
polymers, physical mixture and the statistically optimized HME
film were weighed and sealed separately in crimped aluminum
pans (Kit 0219-0062, Perkin-Elmer Instruments, Shelton, CT).
The samples were heated from 50 to 275  C at a ramp rate of
20  C/min under nitrogen purge at a flow rate of 20 mL/min.
Evaluation of physico-mechanical properties
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Six film samples from each formulation were cut to size, weighed
individually and the average weight was recorded. The thickness of
the same samples was measured using digital gauge (Mitutoyo,
Hitachi, Japan). These film samples (each with an approximately
2.011 cm2 area) from each of the formulations (n ¼ 3) were cut into
small pieces, weighed, transferred into a 100 mL volumetric flask,
allowed to dissolve in 2 mL of dimethyl formamide and adjusted to
100 mL volume with 0.1 N hydrochloric acid solution. The solution
was filtered through 0.45 mm membrane filters and the drug content
was analyzed using UFLC. Mechanical properties of the hot-melt
extruded DOM films were evaluated using a microprocessor based
advanced force gauze with a motorized test stand (Ultra Test,
Mecmesin, West Sussex, UK) and fitted with a 25 kg load cell.
Mechanical properties of the HME films such as tensile strength
(TS) and elongation at break (E/B) were determined as per the
procedure described in one of our earlier published work26.
Bioadhesion
The drug-loaded statistically optimized HME polymeric film was
subjected to in vitro bioadhesion test. The adhesive binding of the
drug-loaded film samples to porcine buccal mucosa was studied
in triplicate using a microprocessor based advanced force gauge
with a motorized test stand (Ultra Test) fitted with a 5 kg load
cell26,27. The work of adhesion and the peak detachment force was
calculated using data plot software.
Additionally, the in vivo residence time studies involved six
healthy volunteers aged between 22 and 30 years in the study.
Circularly cut HME film sample was applied manually by
pressing them against the cheek for about 30 s, without moisten-
ing before application28,29. The time of the patch application,
surface pH, redness and/or mucosal irritation, and the time and
circumstances at the end of adhesion (erosion or detachment of
the film) was recorded for each volunteer in the study.
Swelling and erosion studies
Swelling and erosion studies were conducted to determine the
drug release mechanism from the optimized HME CR (SOCR)
film in phosphate buffer pH 6.6. The film was attached to
preweighed glass supports using a cyanoacrylate adhesive sealant
and immersed in phosphate buffer at 37  C. At predetermined
time intervals (0.5, 1, 1.5, 2 and 3 h), the devices were removed
from the media, blotted with tissue paper to remove excess
surface water and weighed. After determining the wet weight, the
patches were dried at 40  C until constant weight. Swelling index
Drug Dev Ind Pharm, Early Online: 1–12
(SI) and weight loss were determined gravimetrically according to
the following Equations (1) and (2)
wet weight  original dry weight
Swelling index ¼  100, ð1Þ
original dry weight
Erosion ð%Mass lossÞ
original weight  remaining dry weight ð2Þ
¼  100:
original weight
Ex vivo drug permeation
Ex vivo permeation of DOM from the each and statistically
optimized HME CR film was studied across the porcine buccal
membrane using Franz diffusion cell. The buccal film was placed
over the buccal membrane, and the entire set-up was placed over
magnetic stirrer and the experiment was carried out at 37 C.
Samples of 1 mL were collected at predetermined time intervals
from receptor compartment and replaced with an equal volume of
fresh solution and analyzed by UFLC.
In vivo bioavailability study in humans
The study protocol was reviewed and approved by the institutional
human ethical committee, University College of Pharmaceutical
Sciences, Kakatiya University, Warangal, India. In vivo bioavail-
ability study was conducted in 12 healthy male volunteers. The
bioavailability of the statistically optimized bioadhesive HME
buccal film (SOCR) was compared with the marketed tablet
formulation. The volunteers participated in the study were
nonalcoholic and had no other medication for at least 2 weeks
prior to the study. Volunteers were allowed free access to food and
water, until the night prior to dosing and were fasted for 10 h.
Latin square cross-over design was followed; volunteers were
divided into two groups, each group consisting of six volunteers.
In first phase, one group was administered with marketed tablet
formulation, while the bioadhesive HME CR buccal film was
applied to the other group. In second phase, vice versa was
followed and was conducted after 2 weeks of wash out period.
Blood samples (5 mL) were collected at preset time intervals of 0,
0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h. All blood samples were
allowed to clot and centrifuged for 10 min at 5000 rpm (MIKRO
220 R, Hettich, Tokyo, Germany). The serum was separated and
transferred into clean micro-centrifuge tubes and stored at 20  C
until further analysis performed utilizing UFLC.
Pharmacokinetic analysis
Pharmacokinetic parameters of DOM after administration of
bioadhesive buccal HME CR film and marketed tablet formula-
tions were estimated for each volunteer using a computer
program, KINETICA 2000 (Version 3.0, Innaphase Corporation,
Philadelphia, PA). Noncompartmental analysis was used to
calculate the pharmacokinetic parameters: mean peak plasma
concentration (Cmax), time to reach peak plasma concentration
(Tmax), and area under the curve (AUC). The relative bioavail-
ability (F) for buccal delivery was calculated using Equation (3).
½AUC HME buccal film formulation
Relative bioavailability ¼ :
½AUC Marketed tablet formulation
ð3Þ
Ex vivo–in vivo correlation
The cumulative amount of DOM permeated across the porcine
buccal membrane ex vivo from the chosen optimal buccal HME
 DOI: 10.3109/03639045.2015.1104346 Domperidone hot-melt extruded buccal films 5

CR film was compared against the extent of absorption, i.e.
cumulative AUC values for a possible ex vivo–in vivo correlation.
Stability studies
Statistically optimized HME formulation was stored in borosili-
cate glass bottles, flushed with nitrogen, and kept under stability
at 40  C/75% RH for a period of 6 months. Samples were
withdrawn at predetermined time intervals up to 6 months and
analyzed for drug content, in vitro drug release and ex vivo drug
permeation across the porcine buccal mucosa.
Results and discussion
Drug penetration studies
The permeation of drug through the porcine buccal membrane
was observed to be uniform throughout the study and the results
of DOM solution permeation through porcine buccal membrane
are shown in Figure 1. The tissue was isolated successfully as
there was no evidence of detectable levels of phenol red in the
receiver compartment whereas DOM could penetrate freely.
Downloaded by [narendar Dudhipala] at 11:46 07 November 2015
Y3 ðP6 Þ ¼ þ 67:05  9:08  X1 þ 0:26  X2  1:33
ð6Þ
 X1 X2  0:74  X12  3:19  X22 :
In general, the sign and value of the quantitative effect
represents tendency and magnitude of the term’s influence on the
response, respectively30. In regression equation, a positive value
indicates an effect that favors the optimization due to synergistic
effect, while a negative value indicates an inverse relationship or
antagonistic effect between the factor and the response.
Regression values represent the quantitative effect of process
variables: X1, X2 and their influence on the dependent responses:
Y1, Y2 and Y3.
The responses of all the formulations were fitted to linear,
interaction or quadratic models using DOE software. A quadratic
model is suggested for TS, Q6 and P6. The calculated R2 (Table 3)
values for all the responses ranged from 0.7761 to 0.9890
indicating a good model. The adjusted and predicted R2 values
were 0.9705 and 0.8795 for Y1, 0.9812 and 0.9226 for Q6, 0.9415
and 0.7580 for P6, respectively. In all the responses, the adjusted
and predicted R2 values are in reasonable agreement (the
difference between these values always below 0.2 as per DOE

Cumulative percentage amount of DOM permeated in 8 h was

found to be 82.58%, while the flux and permeability coefficient of requirement). When observed value of R2 was at least 0.80, it
DOM were calculated to be 0.618 mgh1 cm2 and 0.051 cmh1, implied a good correlation and was found in all cases, indicating a
respectively. good fit by the model31. Analysis of variance for the responses
indicated that the quadratic regression model was significant and
Statistical analysis of the data and validation of the model valid for each of the responses Y1 (p50.0001), Y2 (p50.0002)
and Y3 (p50.0001) and hence was appropriate to represent the
The regression equations (4–6) were obtained by Design Expert observed data, respectively.
software over the range of independent variables from the random
order in Table 2 from the response surface model. 3D plots
Y1 ðTSÞ ¼ þ 3:87 þ 0:85  X1 þ 0:11X2 þ 0:022  X1 X2 The independent variables, i.e. concentration of PEO N750 (X1)
ð4Þ and concentration of HPMC E5 (X2) and their interaction on the
 0:44  X12  0:24  X22 ,
TS (Y1), Q6 (Y2) and P6 (Y3) as dependent responses were
graphically represented by 3D surface plots by using RSM are
shown in Figure 2.
Y2 ðQ6 Þ ¼ þ 99:7  10:7  X1  0:087  X2  0:20 When TS (Y1) was indicated as the response, good correlation
ð5Þ
 X1 X2  2:77  X12  3:86  X22 , was shown between observed and predicted value as revealed by
r2 of 0.982 (Table 2). This Y1 was significantly influenced by
concentration of PEO N750 (X1), concentration of HPMC E5
(X2), and their interactive term (X1X2) and polynomial model of
lipid concentration X12 with a p50.0001. Magnitude of the
positive coefficient (3.87) of the term is suggesting that elevated
levels of polymer concentrations in the formulation could increase
the TS of films drastically. Figure 2(A) and (B) shows the
response surface model for TS in response to the investigated
factors and had positive influence.
For the 13 formulations, the various factor combinations
resulted in varied in vitro release and permeation from 79.44% to
108.5% and 49.65% to 79.34%. From Figure 2(C)–(F), independ-
ent variables exhibited a linear relationship. Increase in the
concentration of polymer results in decreasing the drug release
and permeation. The concentration of PEO shows marginal effect
on the drug release and permeation, but HPMC had the positive
effect on the permeation (+0.26 from Equation (6) the value of) of
Figure 1. Ex vivo drug permeation studies through porcine buccal
membrane.
drug from films.

Table 3. Regression values represent the quantitative effect of process variables for responses.

Y1 (TS) Y2 (Q6) Y3 (P6)

2 2 2 2 2 2 2
Model R Adjusted R Predicted R R Adjusted R Predicted R R Adjusted R2 Predicted R2
Linear 0.7761 0.7314 0.6245 0.8578 0.8293 0.7667 0.8633 0.8360 0.7378
FI 0.7764 0.7019 0.4226 0.8579 0.8106 0.6794 0.8726 0.8301 0.7184
Quadratic 0.9828 0.9705 0.8795 0.9890 0.9812 0.9226 0.9659 0.9415 0.7580
p Value 0.0001 0.0001 0.0002
 6 C. R. Palem et al. Drug Dev Ind Pharm, Early Online: 1–12
Downloaded by [narendar Dudhipala] at 11:46 07 November 2015

Figure 2. Contour plots showing the interactive effects of (i) concentration of PEONF750 (X1) and HPMC E5 (X2) on tensile strength (Y1), (A and B);
(ii) concentration of PEONF750 (X1) and HPMC E5 (X2) on percent drug release at 6 h Q6 (Y2), (C and D) and (iii) concentration of PEONF750 (X1)
and HPMC E5 (X2) on percent drug permeated at 6 h P6 (Y3), and corresponding response surface plots (E and F).

Optimization of independent variable and validation approach (a numerical optimization technique by the desirability
function and a graphical optimization technique by the overlay
After analyzing the polynomial equations, depicting the depend-
plot). The optimized formulation was obtained by applying
ent and independent variables, a further optimization and
constraints on both dependent and independent variables. The
validation process by means of the design expert software was
constraints were: TS 3.4–3.8 kg/mm2, Q6 95 ± 5%, and P6
undertaken with desirable characteristics to probe the optimal
65 ± 5%. These constrains remained same for all the formulations.
formula solution of DOM CR film. All the responses were
The recommended constraints of the independent variables were
optimized with different targets by a multicriteria decision
 DOI: 10.3109/03639045.2015.1104346
calculated by the DOE software. From the desirability plot, the
desirability was found to be 0.993. The extensive grid and
feasibility searches provided the selection of optimum formulation
by using desired response plot and over lay plot, respectively.
The optimum values of selected independent variables
obtained by using DOE software were 68.77 mg of PEO N750
(X1) and 15 mg of HPMC E5 (X2). Therefore, in order to confirm
the predicted model, a new batch of DOM film according to the
optimal formulation factor levels was prepared and had TS of
3.86 ± 1.20 kg/mm2, Q6 93.62 ± 2.84% and P6 63.36 ± 2.12%. The
observed responses of HME controlled release film of DOM was
in close agreement with the model predictions and the relative
errors (%) were calculated (Table 4). The experimental values
were in agreement with the predicted values confirming the
predictability and validity of the model.
Thermal gravimetric analysis (TGA)
Thermal gravimetric analysis (TGA) thermograms represent
temperature on X-axis and percentage weight loss on Y-axis and
are shown in Figure 3. Pure drug, physical mixture and the
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statistically optimized HME CR film were subjected to TGA
analysis, no sign of thermal degradation or decrease in weight was
observed for all of the samples tested, over the entire period of
Table 4. Comparison of predicted and experimental values of HME CR
film of DOM.
Predicted
Variable value Experimental value Relative error (%)
2
TS (kg/mm ) 3.8 3.86 ± 1.20 1.55
Q6 90.78 93.62 ± 2.84 3.03
P6 60.07% 63.36 ± 2.12 5.19
Notes: TS, tensile strength (kg/mm2); Q6, drug released at 6 h (%);
P6, drug permeated at 6 h (%).
Figure 3. TGA thermograms of (a) domperidone, (b–d) physical mixtures of DOM: PEO NF750, DOM: HPMC E5 and DOM + PEO NF750 + HPMC
E5, (e) hot-melt extruded statistically optimized controlled release (SOCR) film.
Domperidone hot-melt extruded buccal films 7
study. These results indicate that the pure drug and the physical
mixture, including that the produced HME formulation were very
stable when subjected to thermal processing (employed extrusion
conditions).
SEM studies
To further confirm our findings and assumptions, visualization of
the crystal dissolution process of DOM in PEO at elevated
temperature was performed by using a polarized microscope
equipped with hot-stage, whereby morphological changes can be
directly observed. Scanning electron microscopy (SEM) images
are shown in Figure 4(A)–(D), after heating the PEO: drug blend
from room temperature to 275  C at a ramp rate of 20  C/min
(same as in DSC experiments), then cooling down to room
temperature.
At the start of heating DOM crystals were clearly visible,
while PEO appeared as dark-colored particulates. After the
sample was heated to 70  C (slightly above the PEO melting
point), PEO melting became apparent, forming round-shaped
droplets, and DOM became surrounded by the PEO as shown in
Figure 4(B) and started to melt, whereas crystalline DOM not in
contact with melted PEO remained in the original shape. Melting
of such isolated crystals started upon heating to 270  C. At 270  C
all melted materials started to flow freely, became homoge-
neously distributed to cover the entire view field. The visual
observation again demonstrated that DOM and PEO became
miscible at elevated temperature and stayed in a miscible state
upon cooling to room temperature. Crystalline structures of the
drug completely disappeared, forming drug polymer dispersion.
DSC analysis
DSC thermograms for pure DOM, excipients present in CR film,
physical mixture and statistically optimized HME film formulation
are presented in Figure 5. The onset of melting endotherms of PEO
 8 C. R. Palem et al. Drug Dev Ind Pharm, Early Online: 1–12

Figure 4. Micrographs of the (A) pure

polymer, (B) drug-loaded physical mixture,
(C) blank film formulation, (D) drug-loaded
statistically optimized HME CR film
obtained utilizing SEM.
Downloaded by [narendar Dudhipala] at 11:46 07 November 2015

Figure 5. DSC thermograms of domperidone, PEO N750, vitamin E succinate, Physical mixture and statistically optimized hot-melt extruded CR film.

and the drug was observed at 62  C and 251  C, respectively.
The thermogram containing drug–polymer physical mixture
represents a small DOM melting peak (249  C), indicating
immiscibility of the drug in the polymer matrix. In addition, the
heat of fusion for DOM in physical mixture and HME CR film was
observed to be much less than that of the pure drug, which can be
attributed to the relatively lower amount of the drug (10%) present
in the small sample (1–2 mg) taken for analysis compared to the
pure drug. However, the drug’s melting endotherm had essentially
completely disappeared in the statistically optimized HME film,
 DOI: 10.3109/03639045.2015.1104346 Domperidone hot-melt extruded buccal films 9

demonstrating the loss of drug crystallinity in the molten PEO

resulting in the formation of a solid dispersion. The DSC findings
did not reveal any drug-excipient incompatibility, and these results
along with the estimated solubility parameter values from the
molecular structures of the individual components demonstrated
that PEO melt can effectively dissolve the drug, forming a solid
dispersion and/or solution.

Physico-mechanical properties of HME DOM films

Statistically optimized HME DOM film was smooth in appear-
ance, uniform in thickness, mass and drug content and showed no
visible cracks. The weight of the films ranged from 99.6 to
102.4 mg and the thickness ranged from 780 to 830 mm (Table 2).
The drug content in the buccal films ranged from 97.8% to 99.6%,
indicating the favorable drug loading and film uniformity with
respect to drug content. Elongation at break was ranging from
33.2 to 42.2 mm2.
An ideal buccal film should have a relatively high TS and
E/B32. The results of the mechanical properties, i.e. TS and E/B, Figure 6. In vitro drug release and ex vivo permeation profiles of SOCR
HME film (mean ± SD, n ¼ 3).
are presented in Table 2. Maximum TS of 3.86 kgmm2 and E/B
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of 42.8% mm2 was exhibited by statistically optimized formula-

tion, and these results were found to be statistically significantly Table 5. Domperidone estimated values of release exponent (n) and
different (p50.05) compared. The relatively high TS and E/B correlation coefficients (r2), from HME CR formulations.
values of the optimal formulation (CR) are due to difference in the
polymer concentration in the formulation and best suits for buccal Correlation coefficient values (r2) Korsmeyer–Peppas
delivery.
Formulation Zero order First order Higuchi n
In vitro release studies CR1 0.819 0.963 0.979 0.966 0.496
CR2 0.823 0.973 0.981 0.971 0.486
In vitro dissolution profiles of HME DOM CR formulations CR3 0.867 0.995 0.993 0.991 0.5
prepared were ranging from 79.44% to 108.5%. The differences in CR4 0.904 0.863 0.992 0.989 0.533
drug release patterns from different HME CR formulations were CR5 0.907 0.899 0.991 0.989 0.54
related to the differences observed in the swelling indices and CR6 0.904 0.866 0.992 0.991 0.54
erosion behavior of the HME films as a function of the polymer CR7 0.88 0.969 0.995 0.994 0.461
CR8 0.906 0.989 0.996 0.994 0.551
type and concentration. Overall, the differences in the drug CR9 0.897 0.984 0.997 0.995 0.495
release amongst the three formulations could be primarily CR10 0.907 0.854 0.991 0.99 0.539
ascribed to the presence of different polymer types in varying CR11 0.848 0.784 0.984 0.984 0.479
concentrations in the formulations. The drug release profile from CR12 0.831 0.944 0.977 0.98 0.477
SOCR film was 93.62% in 6 h and shown in Figure 6. CR13 0.905 0.984 0.991 0.989 0.542
The release kinetics was studied for all the controlled release SOCR 0.878 0.989 0.997 0.996 0.497
HME CR formulations and is shown in Table 5. The results Notes: SOCR, statistically optimized controlled release film.
indicate that the release from the statistically optimized HME CR
(SOCR) formulation followed the Higuchi-matrix model as
evidenced from the correlation coefficient value Also, the release
detachment force (1.75 N) and in vivo residence time (5.5 h).
mechanism of DOM from the HME CR formulations was studied
The subjective parameters such as irritancy, discomfort, dry
by fitting the data in the equation proposed by Korsmeyer et al.33
mouth, salivation, dislodgment of the HME DOM CR film during
Mt the study and heaviness of the formulation at the place of
¼ Ktn , ð9Þ attachment were recorded from the volunteers after completion of
M
the in vivo residence time study. No volunteer has reported any
where ‘‘Mt/M’’ is the fractional amount of drug release at any irritancy due to film (evident from no alteration in the surface pH
time ‘‘t’’, ‘‘k’’ is the release rate constant, and ‘‘n’’ is the release and/or no redness at the application site observed before and after
exponent that characterizes the type of the release mechanism the film placement in the oral cavity) during study; no volunteer
during the dissolution process. The value of ‘‘n’’ was estimated by felt uncomfortable and slight salivary secretion during study. No
linear regression of log (Mt/M) versus log t, and is listed in volunteer felt dryness of the mouth and heaviness of the buccal
Table 5. For non-Fickian release, the n value falls between 0.5 and patch at the place of attachment, because of the moderate
1.0, while in the case of Fickian diffusion, n ¼ 0.5; for zero-order thickness and low weight of the patch.
release (case II transport), n ¼ 1; and for supercase II transport
n41. The statistically optimized HME CR formulation showed Swelling and erosion studies
Higuchi model (r2 ¼ 0.997) release mechanism as its n value was
calculated to be 0.49. The results of the swelling index studies demonstrated that the
extrudates of PEO matrices rapidly absorbed the aqueous medium
and increased in weight over the time until its complete
In vitro bioadhesion
disintegration around 7 h. Statistically optimized HME CR
In vitro bioadhesion and in vivo residence time for statistically formulation showed the highest swelling index 240.4%. SI
optimized HME CR formulation was conducted and displayed depends on the rate of polymer hydration in a given
good bioadhesion, i.e. work of adhesion (3.21 mJ), peak medium34,35. The drug release from a hydrophilic matrix will
 10 C. R. Palem et al.
Figure 7. Erosion profile of the SOCR HME film (mean ± SD, n ¼ 3).
be followed by the bulk hydration and gel formation of the
polymers due to solvent penetration. Upon complete hydration of
the outer layer, the hydrated gel layer starts to disperse or dissolve
due to attrition process. This process is termed as erosion and it is
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mainly controlled by the strength of the formed gel layer. The
stronger the gel layer, the slower is the erosion and vice versa. The
results of the erosion studies for the optimal CR formulation are
presented in Figure 7. The percent weight loss from the extruded
PEO-HPMC matrix increased with time, and completely eroded at
the end of seven hours.
Ex vivo drug permeation from controlled release HME film
The results of ex vivo drug permeation through porcine buccal
membrane from controlled release HME films were ranging from
49.65% to 79.34%. The cumulative percentage of drug permeated
in 6 h, flux and permeation coefficient from the SOCR formu-
lation was found to be 63.36%, 0.638 mg h1 cm2, 0.04 cmh1,
respectively (Figure 6). The results of the drug permeation reveal
that DOM was released from the formulation and permeated
through porcine buccal membrane, and hence could possibly
permeate through the human buccal membrane.
In vivo bioavailability studies
The mean serum plasma concentration–time profiles of DOM
following application of bioadhesive HME CR buccal film
(SOCR) and marketed tablet are shown in Figure 8 and Table 6.
Analysis of serum samples by UFLC did not show any
interfering peaks. Both DOM and internal standard (propranolol
hydrochloride) could be eluted without any interference. The
method employed for the assay was quite sensitive and significant
serum levels of DOM could be detected for 12 h. Since 1.0 mL of
serum was taken for extraction, the DOM levels could be detected
much comfortably.
The higher Cmax value and delayed in Tmax value were
observed for SOCR formulation compared to the orally admin-
istered marketed tablet formulation. The mean Cmax and Tmax for
DOM was calculated to be 79.9 and 145.7 ngmL1; 2.18 and
5.25 h, respectively, after administration of marketed tablet and
bioadhesive buccal HME SOCR film. The Tmax of the marketed
dosage form was found to be relatively faster compared to the
SOCR formulation. This may be attributed to the peroral
administration, where DOM is immediately available for absorp-
tion; however, the buccal formulation, similar to a matrix
formulation, has DOM embedded in a polymeric matrix of PEO
and HPMC E5. This could cause a little delay in drug release/
dissolution from the polymeric matrix prior to being readily
Drug Dev Ind Pharm, Early Online: 1–12
Figure 8. Mean serum profiles of DOM in healthy human volunteers,
after administration of oral marketed tablet and SOCR HME film
(mean ± SD, n ¼ 6).
Table 6. Pharmacokinetic parameters of domperidone in healthy human
male volunteers after administration of marketed tablet and statistically
optimized HME CR (SOCR) film.
Parameter Marketed tablet SOCR
Cmax (ng/mL) 79.98 ± 14.1 145.7 ± 19.2*
Tmax (h) 2.18 ± 0.53 5.25 ± 1.03*
AUC0–24 (ng h/mL) 277.1 ± 62.44 911.2 ± 77.8y
AUCTotal (ng h/mL) 281.2 ± 60.08 917.1 ± 79.7y
*Statistically significant at p50.001.
yStatistically significant at p50.0001 compared with marketed tablet.
available for absorption. The mean AUC0–24 and AUCTotal for
DOM were found to be 277.1 and 281.2 ngh mL1; 911.0 and
917.8 ngh mL1 after administration of marketed tablet and
SOCR film formulations, respectively. The overall mean values
of AUC0–n are 3.29 times higher for buccal route compared to the
oral route, which indicates an improvement of bioavailability of
DOM, when administered in the form of HME controlled release
buccal delivery system.
Ex vivo–in vivo correlation
Ex vivo–in vivo correlation between the cumulative amount of
drug permeated across the porcine buccal membrane and AUC for
SOCR HME film showed a biphasic curve pattern (Figure 9),
which can be distinguished into two regions for DOM. Good
linear correlation was observed with correlation coefficients,
r2 ¼ 0.947 during lag phase and r2 ¼ 0.982 during absorption
phase. Point to point correlation of ex vivo permeation of drug to
in vivo performance was observed, indicating that it follows ‘‘type
A’’ correlation. The slow permeation and/or absorption of DOM
through porcine buccal membrane in the initial stages could be
explained as follows: in the first phase, DOM released from the
formulation permeates through buccal membrane and deposition
of DOM occurs in the membrane layers, which ultimately result in
the concentration build-up at that site. Drug permeation and the
concentration build-up in buccal membrane are represented by the
lag phase observed in first region. This accumulated drug in the
membrane causes flux establishment and results in the faster drug
absorption or AUC increase at a rapid rate, during the second
phase36.
 DOI: 10.3109/03639045.2015.1104346 Domperidone hot-melt extruded buccal films 11
Figure 9. Ex vivo–in vivo correlation of
cumulative amount permeated ex vivo
versus AUC for the SOCR HME film
formulation.
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Table 7. Accelerated stability study data of the statistically optimized

release, ex vivo permeation through porcine buccal membrane,
HME CR (SOCR) formulation. and good bioadhesive properties. In vitro residence time in human
volunteer study results revealed that the optimized formulation
Stability parameters of SOCR film formulation exhibited a good retentive property leaving no sign of irritation at
the application site on buccal mucosa. Results of the bioavail-
Cumulative ability study showed an improved permeation of DOM from the
Drug Content* % Drug % drug
Time (mg) released* (Q6) permeated* (P6) hot-melt extruded buccal formulation compared with marketed
tablet. An improved bioavailability by the HME formulation at an
Initial 9.96 ± 0.16 93.6 ± 2.84 63.36 ± 2.12 extent of 3.29-fold higher than that of the oral formulation was
1 Month 9.95 ± 0.18 93.4 ± 3.28 63.42 ± 2.32 observed. Hence, the development of bioadhesive HME buccal
2 Month 9.94 ± 0.23 93.7 ± 3.82 63.17 ± 3.63
3 Month 9.91 ± 0.36 93.9 ± 3.18 63.52 ± 2.84 films could be very promising in improving the bioavailability of
6 Month 9.85 ± 0.42 93.2 ± 3.66 63.34 ± 3.15 poorly soluble drugs, as well as reducing the necessary drug dose,
thus minimizing the side effects associated with the drug. Good
a
Mean ± SD, n ¼ 3. ex vivo–in vivo correlation was also observed for the optimal
formulation. The results of this study indicate that HME is
a viable technique for the development of mucoadhesive
Stability study buccal films containing DOM with improved bioavailability by
The stability of the optimized HME formulations was investigated using RSM.
as per ICH guidelines. The formulations were stored in
accelerated condition (H4) at a temperature of 40 ± 2  C and
75 ± 5% relative humidity (RH) up to 6 months. The results of the Declaration of interest
stability studies revealed that there was no significant change in The authors report no conflicts of interest. One of the authors (Dr. Chinna
drug content, in vitro drug release, and ex vivo permeation across Reddy Palem) thanks University Grant Commission (UGC), New Delhi
the porcine buccal membrane (Table 7). Less than 5% of drug loss for providing UGC major research project [F.No.: 32–134/2006(SR)].
was observed for optimized film formulation at the end of 6
months, when placed under H4 condition. The statistically References
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