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Research J. Pharm. and Tech. 14(10): October 2021
5133
ISSN 0974-3618 (Print) www.rjptonline.org
0974-360X (Online)
RESEARCH ARTICLE
Development and Evaluation of Trans Buccal Patches based on Natural and
Synthetic Polymers Loaded with Rivastigmine using Solvent Casting
Technique
Prasanta Kumar Mohapatra1
*, Boddu Pavan Kumar2
, Pankaj Singh Patel1
,
Harish Chandra Verma1
, Satyajit Sahoo3
1
Moradabad Educational Trust Group of Institutions, Faculty of Pharmacy, Moradabad - 244001, Uttar Pradesh, India.
2
Lydia College of Pharmacy, Ravulapalem - 533238, Andhra Pradesh, India.
3
C. U. Shah College of Pharmacy and Research, Surendranagar - 363001, Gujrat, India.
*Corresponding Author E-mail: mohapatra.kjr@gmail.com
ABSTRACT:
Mucoadhesive buccal films of rivastigmine were prepared by the solvent casting technique using HPMC K15M,
sodium alginate, glycerine, and Eudragit RL100. Arranged films assessed for weight variation, thickness, % drug
substance, % moisture loss, % moisture take-up, folding endurance, in-vitro medicament release, and Fourier
transform Infrared spectroscopy (FTIR). The films showed a controlled release (CR) over 8 h. The preparation
observed to be a worthy candidate for the development of buccal patches for therapeutic purposes. Drug-polymer
compatibility considers FTIR demonstrated no contradiction between the medicament and the polymers. The
optimized formulation found F7 indicated drug release 85% at the end of 8 h. Thinking about the correlation
coefficient (R2) values got from the kinetic equations, the drug release from the formulations F1-F8 has
discovered zero-order release mechanism. It can be concluded that oral buccal patches of rivastigmine, for
treatment of Alzheimer’s and Parkinson’s disease, can be formulated. The study suggests that rivastigmine can
be conveniently administered orally in the form of buccal patches, with the lesser occurrence of its side effects
and improved bioavailability.
KEYWORDS: Buccal Patches, HPMC K15M, Sodium Alginate, Eudragit RL100, Solvent Casting Technique.
INTRODUCTION:
The drug delivery systems (DDSs) generally comprise
tablets, suspension, cream, ointment, liquid, injectable,
and aerosol. Today widely used DDSs are conventional
DDSs. The methods that apply to get the therapeutic
agent in the human body known as drug delivery. The
delivery system’s other role is to allow the safe
application of the drug. So, in the formulation, the
medicament must be physically, synthetically, and
microbiologically steady. By the use of suitable DDSs,
the side effects of the drug and drug interactions should
be minimized or avoided. The convenience of drug
administration should be improved by the delivery
systems1
.
Received on 20.04.2020 Modified on 12.10.2020
Accepted on 19.01.2021 © RJPT All right reserved
Research J. Pharm. and Tech. 2021; 14(10):5133-5140.
DOI: 10.52711/0974-360X.2021.00894
Any drug delivery system (DDS) attains the release of
the drug over a prolonged period known as a sustained-
release drug delivery system (SRDDS), which is not
time-dependent. In formulating a sustained-release (SR)
dosage form hydrophobic polymer matrix commonly
used. The character of the ultimate DDS is to provide an
accurate site of action to maintain the therapeutic range
of drug in blood plasma and to deliver the right amount
of medicament at a regular time intermission. The most
famous form of controlled release drug delivery system
(CRDDS) is an oral CRDDS, and it is the clear
advantage of the oral route of drug administration. Such
methods release the drug with a steady or fluctuating
release rate. A typical pattern of drug release shown by
the oral CRDDS, an extended period, and the drug
concentration maintained in the therapeutic window. The
better control of plasma drug levels, less side effect,
fewer dosage frequencies, increased efficacy, and
continuous transfer, delivered by CR dosage form2,3,4
.
The plasma concentration of drugs within the therapeutic
Research J. Pharm. and Tech. 14(10): October 2021
5134
window, for an extended time maintained by CRDDS, to
confirm sustained therapeutic action and for that
purpose, a growing interest in their growth exists in
hypothetical drug concentration profiles, then single
doses of immediate-release, SR, and control release drug
delivery systems (CRDDSs)5
. The active agents mainly
released from a delivery system by three primary
mechanisms are diffusion, swelling, and degradation
followed by diffusion. When a drug or other active agent
permeates through the polymer by a diffusion
mechanism that creates the CR device. In the polymer
matrix or on a molecular level or by passing between
polymer chains on a macroscopic scale as through pores,
the diffusion can occur6
. The CRDDSs have created and
developed for controlling the rate of drug delivery,
targeting the delivery of a drug to tissues, and/or
sustaining the duration of therapeutic activity7
. An
important route of drug administration has lately
discovered is a buccal drug delivery (BDD). For BDD,
several bio-adhesive mucosal dosage forms developed,
like gels, ointments, adhesive tablets, patches, and more
recent film. In the mid-1980's the idea of mucosal
adhesive or mucoadhesive introduced into the CRDDS.
The adhesive attached to mucosal is natural or synthetic
polymers that intermingle with the mucus layer cover up
the epithelial surface of mucosal and mucin molecules,
which is organizing a major part of the mucus8
. The
likelihood that these polymers can be utilized to defeat
physiological boundaries to long-term drug delivery, this
idea of mucoadhesive has informed by numerous
investigators9
. The investigators made the treatment
safer and more effective, not only for topical disorders
but also for systemic difficulties10
. An
Acetylcholinesterase Inhibitor drug rivastigmine inhibits
both Acetylcholinesterase and Butyrylcholinesterase
(unlike Donepezil, which selectively inhibits
Acetylcholinesterase). It is better to work by preventing
these cholinesterase enzymes, which would otherwise
collapse the brain Neurotransmitter acetylcholine11
. The
established treatment effects of rivastigmine have on the
cognitive (memory and thinking), functional (activities
of daily living) and behavioral problems generally linked
with Alzheimer's12,13,14
and Parkinson's disease
dementias15
. Orally or via a transdermal patch the drug
rivastigmine can be administered; the latter decreases the
occurrence of side effects,16
which typically consist of
nausea and vomiting17
. The drug rivastigmine is excreted
through the urine and performs to have relatively rare
drug-drug interactions17
. It is a white to off-white, fine
crystalline powder i.e., both hydrophilic (soluble in
water) lipophilic (soluble in fats) and it arises in a
multiplicity of administrations, including a capsule,
solution, and transdermal patches. Comparable to other
Cholinesterase Inhibitors17
bio-adhesive patches are used
in the mouth, which releases the drug after contact with
oral mucosa and absorbs directly by entering into a
systemic solution. The patches are commonly prepared
by a solvent evaporation technique18
. The objective of
this study was to prepare rivastigmine mucoadhesive
buccal patches and evaluate their properties.
MATERIALS AND METHODS:
Materials:
Rivastigmine was procured as a gift sample from Indian
Immunologicals Ltd, Gachibowli, Hyderabad, India. The
Eudragit RL100 and HPMC K15M Purchased from Otto
Chemicals and Oxford Chemicals. Sodium alginate,
plasticizer, and glycerine procured from Rankem Pvt
Ltd, India. All other chemicals are of analytical grade,
procured from the authorized dealer19,20,21,22
.
Drug-polymer Compatibility:
To explore any conceivable collaboration between the
medication and the used polymers under scrutiny, FTIR
spectrophotometer strategy utilized. In FTIR study the
pure drug rivastigmine and a physical blend of pure drug
and polymers accomplished on Tensor 27, Bruker
Optics, Germany by a KBr dispersion method. The 400
cm-1
to 4000 cm-1
range selected for FTIR spectra (Fig. 3
and 4 )23,24,25,26
.
Determination of λ Max of Rivastigmine in 6.8 pH
Buffer:
The required quantity (100mg) of pure drug rivastigmine
dissolved in 6.8 pH to make a solution of 1000µg/ml in a
100ml volumetric flask. By diluting the above solution
to 10µg/ml, then the solution scanned between 200-
400nm range to get maximum absorption. From the
spectra of drug rivastigmine, maximum absorption
262nm selected for the analysis21,27
.
Calibration Curve of Rivastigmine with 6.8
Phosphate Buffer:
A stock solution containing 1mg/ml of the pure drug
prepared by dissolving 100mg of rivastigmine
insufficient 6.8 pH buffer to produce a 100ml solution in
a volumetric flask. From the 1000µg/ml standard stock
solution, 1ml, 2ml, 3ml, 4ml, 5ml of solution were
pipette out into 10ml volumetric flasks. The volume
made up to mark with buffer. These dilutions give 100
µg/ml, 200µg/ml, 300µg/ml, 400µg/ml and 500µg/ml
concentration of rivastigmine, respectively. The
calibration crook fed in the concentration range of 100-
500µg/ml at 262nm. The concentration of the sample
solution by using the calibration curve can be
determined21,24
.
Preparation of Mucoadhesive Buccal Patches:
The Solvent casting method employed to prepare buccal
patches by using HPMC K15M, Sodium alginate, and
Eudragit RL100 as polymers. According to the lot
formula, all the ingredients in hold pharmaceutical,
polymer, and excipients estimated even.
Research J. Pharm. and Tech. 14(10): October 2021
5135
Table 1: Composition of Different Buccal Mucoadhesive Formulations.
Compounds F1 F2 F3 F4 F5 F6 F7 F8 F9
Rivastigmine (mg) 70 70 70 70 70 70 70 70 70
Sodium Alginate (mg) 500 * * 750 * * 325 325 *
Eudragit RL100 (mg) * 500 * * 750 * 325 * 325
HPMC K15M (mg) * * 500 * * 750 * 325 325
Glycerine (ml) 65 65 65 65 65 65 65 65 65
Methanol (ml) * 20 * * 20 * 20 * 20
Water (ml) Up to 30
ml
Up to 30
ml
Up to 30
ml
Up to 30
ml
Up to 30
ml
Up to 30
ml
Up to 30
ml
Up to 30
ml
Up to 30
ml
Note: * the particular excipient not utilized in the formulation
The medicament and all the ingredients have taken on a
butter wallpaper with the aid of a stainless-harden
spatula than the ingredients dissolved in the water
containing measuring glass. After dissolving the drug
and polymers completely, plasticizer and permeation
enhancer added. Then the complete solution transferred
to a petri plate and kept for drying and patches are
collected24,28,29
.
Statistical design:
Most formulation strategy contains the variation of one
factor at a time, keeping other factors steady. Such an
empirical technique is satisfactory, but when factors are
independent of each other. The factorial designs permit
all factors to change, in this way permitting evaluation of
the impact of every factor at each point and indicating
interrelationship among them. A statistical model
encompassing interactive and polynomial expressions
utilized to evaluate the reactions. A factorial design
utilized sequentially to study the outcome of independent
formulation variables (amount of sodium alginate,
Eudragit RL100, HPMC K15M, and Methanol) specified
as factors X1, X2, X3 and X4 on the release profile of
rivastigmine from mucoadhesive buccal patches. Table 2
summarizes a record of the nine-formulations examined,
their factor combinations, and the coded levels of the
experimental units utilized during the study4,34
.
Table 2: Experimental Factorial Design Layout.
Coded
levels
Coded factors and their actual values
X1 =
Sodium
alginate
(mg)
X2 =
Eudragit
RL100
(mg)
X3 =
HPMC
K15M
(mg)
X4 =
Methanol
(ml)
-2 * * * 20
-1 325 325 325 *
0 500 500 500 *
+1 750 750 750 *
Formulation
code
Coded factors and their levels
X1 X2 X3 X4
F1 0 * * *
F2 * 0 * -2
F3 * * 0 *
F4 +1 * * *
F5 * +1 * -2
F6 * * +1 *
F7 -1 -1 * -2
F8 -1 * -1 *
F9 * -1 -1 -2
Note: * the particular excipient not utilized in the formulation
Fig. 1: Photograph of Prepared Mucoadhesive Buccal Patch of
Rivastigmine
Evaluation of the Transdermal Patches:
Physical Appearance:
Mucoadhesive buccal patches visually scrutinized for
color, flexibility, homogeneity, and smoothness19,30
.
Thickness and Weight Variation:
By using a thickness gauge, the thickness of the patch at
three unalike points determined. To decide the mass of
individual patch, the patch separated from the cast patch
and the patches weighed independently utilizing a digital
balance. The weight variation performed by individually
weighing ten randomly selected patches. Same as the test
carried out for each formulation24,29,31,32
.
Folding Endurance:
In the laboratory by designing an apparatus, the folding
endurance test for patches (2cm x 2cm) executed. For the
folding endurance test, the disintegration mechanical
assembly was reworked. For holding the patch, the
device comprises two braces. Out of two clamps, one
clamp was a constant place while another clamp was
moving provision. The movable clamps moved 5cm
distance at a speed of 30rpm. The patch will be slightly
stretched when the patch was at a maximum distance.
Until the patch broke into two pieces, the apparatus
allowed to run. By rpm, the folding was
counted19,24,29,33,34
.
Percentage of Moisture Loss:
Accurately gauged patches of every detailing kept at
room temperature in a desiccator and presented to a
climate having 98% relative humidity (comprise calcium
chloride anhydrous) and it weighed following three days.
In tripled, the test impelled out. Difference between
initial and final weight, the percentage of moisture loss
was calculated25,32,33,35
.
Research J. Pharm. and Tech. 14(10): October 2021
5136
Percentage Moisture Uptake:
In a desiccator accurately gauged patches of every
formulation put at room temperature, which kept up at
79.5% relative humidity (saturated solution of aluminum
chloride) and following three days gauged. In triplicate,
the experiment carried out. Difference between final and
initial weight, the percentage of moisture uptake was
calculated29,30,36
.
Drug Content % Estimation:
Patches of the predetermined zone cut, and the pieces
transferred into a 100ml volumetric flask comprising
phosphate buffer (pH 6.8), and the flask sonicated for 8
h. A blank set up in a similar way utilizing a
medicament-free placebo patch of similar dimensions.
By utilizing a 0.45μm filter, the solution filtered and the
content of the drug analyzed at 262nm by UV-Vis
spectrophotometer9,27,34,37,38
.
In-vitro Drug Release Studies:
The in-vitro release studies impelled out by applying the
diffusion mechanism in a glass beaker with the help of a
modified magnetic stirrer. The compartment maintained
at 37±1°C employing an electric control circulator and
also verified manually by using a thermometer. The
compartment loaded up with newly arranged phosphate
buffer pH 6.8. The solvent in the receptor compartment
persistently mixed at 60 rpm utilizing a Teflon covered
magnetic stirrer, in command to shun diffusion layer
expression. The commercial semi-porous layer mounted
between the giver and receptor compartment and verified
set up by methods for a brace. The patch set on one side
of the semi-penetrable layer. Aliquots of 1 ml were
remote from the receptor pigeonhole by methods for a
syringe and supplanted promptly with a similar volume
of support arrangement kept at 37±1°C. Test samples
taken from the medium at predetermined time intervals
throughout 8 h the samples analyzed for rivastigmine
content by UV-Vis spectrophotometer at 262 nm20,24,28,29
.
Kinetics of Drug Release:
The diffusion kinetics of the rivastigmine analyzed by a
graphical method for zero-order, first-order, Higuchi,
Hixon-Crowell, and Peppa’s exponential equation. To
study the study kinetics, data obtained from the in-vitro
release plotted in various kinetic models4,24,39
.
Zero-order Model:
From the pharmaceutical dosage forms dissolution of the
drug does not disaggregate and release the drug little by
little and the graph plotted as % drug released Vs time in
‘h’ can be expressed by
Qt = Q0 + k0t (1)
Where,
Q0 = Initial concentration of drug at time t = 0
Qt = Amount of drug dissolved at a time t
K0 = Zero-order constant in concentration/time
t = Time in h
First-order Model:
This model is the necessity to decide the absorption
and/or elimination of some drugs, regardless of whether
it is hard to conceptualize this mechanism on a
hypothetical premise. The diagram was a conspiracy as a
log % cumulative drug last Vs time in ‘h’.
Log Qt = log Q0 – Kt / 2.303 (2)
Where,
Qt = Percent of drug remaining at time t
Q0 = Initial concentration of drug
K = First-order constant
t = Time in h
Higuchi Model:
It is a first mathematical model that defines drug release
from a matrix system, recommended by Higuchi in 1961.
The intrigue graph drowned % cumulative drug
discharged Vs square root of time.
Qt = KHt1/2
(3)
Where,
Qt = Amount of drug released at time t per unit area A
KH = Higuchi dissolution constant reflecting design
variable system
t = Time in h
Hixon Crowell Model:
The particles that have a uniformed size, the equation
derived by Hixson and Crowell describes the dissolution
rate based on the weight of the particles cube root and
the particle radius not assumed to be variable.
It is calculated by the equation,
Q0
1/2
- Qt
1/2
= KHt (4)
In the pharmaceutical dosage form, the incipient amount
of medicament is Q0 and the rest of the measure of
medication in the pharmaceutical dosage form is Qt at a
time ‘t’ and ‘KH’ is a Hixson-Crowell proportionality
consistent. From the acquit kinetics, information
acquired from in-vitro medicament release studies
plotted as the cube root of % medicament remaining Vs
time in ‘h’24,39
.
Korsmeyer Peppa’s Model:
Mt/ M∞ = K tn
(5)
Where the quantity of drug release at time t is Mt, and
the amount released at a time is M∞ where t =∞, thus Mt
/ M∞ is the at a time ‘t’ fraction of drug released, the
kinetic constant known as ‘k’, and diffusion exponent is
‘n’ and for both solvent penetration and drug release
mechanism characterized by the above equation. The
correlation coefficient set up by executing the obtained
data into various kinetic models. From the slope, the rate
constants of respective models calculated. The ‘n’
esteem utilized to portray different releases for
mucoadhesive film substances and depicted in Table 5.
For the occasion of film, Fickian diffusion relates when
Research J. Pharm. and Tech. 14(10): October 2021
5137
n ≤ 0.50 and non-Fickian transport relates 0.50 < n <
0.10, Case II (relaxational) transport obey when n =
0.10, and in case of n > 0.10 obeys super case II
transport40,41,42
.
RESULTS AND DISCUSSION:
Calibration Curve Preparation:
Calibration curves of rivastigmine in phosphate buffer
pH 6.8 solutions constructed at λ max 262nm with a
(Shimadzu Corporation, Kyoto, Japan). Beer’s law
obeyed to construct the calibration curve was in the
concentration range of 100-500μg/ml. The analysis done
in triplicate24
.
Table 3: Calibration Curve of Rivastigmine in 6.8 pH Buffer.
Concentration (µg/ml) Absorbance (Mean ±SD)
0 0
100 0.133
200 0.272
300 0.41
400 0.545
500 0.678
Fig. 2: Calibration Curve of Rivastigmine in 6.8 pH Buffer
Physical Appearance:
All the mucoadhesive buccal patches formulated
utilizing different concentrations of polymer were
achieved transparent, uniform, smooth, flexible, and
homogeneous19,30,43
.
Thickness Uniformity:
All the patches have found uniform thickness. The
mucoadhesive buccal film thickness was found between
0.225±1.1 mm to 0.268±1.1 mm24,35,43
.
Percentage of Moisture Loss:
Precisely weighed patches of all formulation held at
room temperature in a desiccator and introduced in an
environment of 98% relative dampness (comprising
anhydrous calcium chloride) and weighed the following
three days. The test moved out in treble. The moisture
loss percentage determined by calculating the difference
between the initial and final weight concerning initial
weight at the dry condition. The achieved values were
between 5.10±0.3% to 12.42±0.4%32,35
.
Percentage Moisture Uptake:
Correctly gauged patches of each formulation placed in a
desiccator and which was 79.5% relative moisture,
previously mentioned (comprise aluminum chloride
saturated solution) at room temperature and following
three days similar patches gauged. The test performed in
triplicate. When the formulations contain standard
moisture content, the film remains stable, non-brittle,
and free from complete drying. The optimum standard of
moisture absorption found in formulation F1, F4 and F7,
so there is less chance of microbial contamination and
maintaining integrity in the entire shelf life. The
percentage of moisture uptake calculated by initial and
final weight and the founded range was 4.64±0.03% to
10.33±0.01% (Table 4)29,35,44
.
Folding Endurance:
An idea about the flexibility or brittleness of films
specified by folding endurance. Good limberness gives
high excellence of folding endurance, but fragility films
give a less value of folding endurance. All the films
didn’t show any crack or cut after over 200 times,
folding according to the obtained results, and all were
having acceptable flexibility. The results observed in
Table 429,35,37
.
Weight Variation Test:
All the film's weight found to be uniform. The weight
found between 99.09±1.1 mg to 100±1.2 mg. It observed
from the obtained results that by increasing the polymer
concentration the weight of the film also increases. Any
deviation in the film's weight leads to under-dosage or
overmedication possessed by a momentary feature
known as weight variation test. The weight results
shown in Table 424,26,35
.
Drug Content Percentage:
The accurate distribution of the drug ensured by the drug
content estimation. For every formulation, the test is
done in triplicate, and arise results were ready in Table 4.
The results indicate that the drug uniformly dispersed
means proper content, uniformity found. The percentage
of drug content found between 92.41±0.1% to
98.59±0.6%24,31,38
.
Drug-polymer Compatibility:
FTIR spectra of pure drug and a mixture of the pure drug
and polymers introduced in Fig. 3 and 4. FTIR spectrum
of pure drug rivastigmine displays the peaks at 666.79
cm-1
, 902 cm-1
, 1125 cm-1
, 1228.33 cm-1
, 1401.33 cm-1
,
and 1691.39 cm-1
. These peaks can be reflected as
characteristic peaks of rivastigmine not affected and
detected in the FTIR spectra of rivastigmine together
with polymers as presented in Fig. 4, which showed that
between drug and polymers there was no interaction24
.
Research J. Pharm. and Tech. 14(10): October 2021
5138
Table 4: Physicochemical Evaluation Data of Rivastigmine Patches.
Formulation
Code
Appearance Surface
Texture
% Moisture
Loss*
% Moisture
Uptake*
Folding
Endurance
Thickness
(mm)*
Weight Variation
(mg)*
% Drug
Content*
F1 + VS 9.36 ± 0.6 4.64 ± 0.05 >200 0.248 ± 0.6 99.87 ± 1.4 94.9 ± 1.3
F2 + VS 8.63 ± 0.4 7.25 ± 0.07 >200 0.225 ± 1.1 99.7 ± 1.9 96.5 ± 0.8
F3 + VS 5.75 ± 0.6 6.04 ± 0.04 >200 0.234 ± 0.8 99.09 ± 1.1 94.5 ± 0.9
F4 + VS 9.36 ± 0.7 4.64 ± 0.06 >200 0.268 ± 1.1 99.87 ± 1.4 96.5 ± 0.8
F5 + VS 8.63 ± 0.8 7.25 ± 0.09 >200 0.256 ± 0.9 99.98 ± 1.2 94.9 ± 0.8
F6 + VS 8.96 ± 0.6 6.04 ± 0.05 >200 0.258 ± 0.7 99.5 ± 1.8 94.28 ± 1.5
F7 + VS 12.42 ± 0.4 4.64 ± 0.03 >200 0.248 ± 0.6 99.7 ± 1.9 93.45 ± 0.8
F8 + VS 5.10 ± 0.3 10.33 ± 0.01 >200 0.225 ± 1.1 99.09 ± 1.1 98.59 ± 1.6
F9 + VS 8.76 ± 0.2 8.18 ± 0.04 >200 0.234 ± 0.7 100 ± 1.2 92.41 ± 0.9
*Each Value Represents the Mean ±S.D. (n=3) (VS = Very Smooth)
In-vitro Drug Release:
The release data of rivastigmine from all the patches
given in Fig. 5, 6 and 7. It indicates that the drug release
time was highest in combinations of sodium alginate and
Eudragit RL100 in F7. At pH 6.8, when contrasted to F1
and F3, the formulation F2, the release rate of the drug is
slow, might be because of the existence of Eudragit
RL100. The data of the in-vitro release fit into different
equations and kinetic models to explain the release
kinetics of rivastigmine from these buccal patches.
Fig. 3: FTIR Sample for Rivastigmine (Pure Drug)
Fig. 4: FTIR Sample for Optimized Formulation
The release kinetics of rivastigmine followed a zero-
order from the patches F1 to F8. The release rate of the
drug in polymers was in this pattern Eudragit RL100 <
sodium alginate < HPMC K15M. From this data, it
found that the release rate found slower by using
Eudragit RL100 than others. Again, the formulations F7,
F8 and F9 made by combining of two polymers and
compared with formulations having more amount of
polymer and it found that a combination of polymers
gives a good result means extended-release, hence the
Research J. Pharm. and Tech. 14(10): October 2021
5139
mechanism of drug release from the rivastigmine patches
followed is dissolution controlled. In the formulations F1
to F9, glycerin used as a permeation enhancer. When
compared to all the formulations it indicated by the
rivastigmine patches in Fig. 5, F7 released 85% of the
drug in 8 h24,28,35
.
Fig. 5: In-vitro Drug Release Profile of F1, F4, F7 Rivastigmine
Buccal Patches
Fig. 6: In-vitro Drug Release Profile of F2, F5, F8 Rivastigmine
Buccal Patches
Fig. 7: In-vitro Drug Release Profile of F3, F6, F9 Rivastigmine
Buccal Patches
Kinetics of Drug Release:
The drug release data then fitted to mathematical models
such as a zero-order, first-order, Higuchi, Hixon-Crowell
and Korsmeyer-Peppas model and the coefficients of
regression values compared. The regression value of
films F1 to F8 follows zero-order and only F9 follows
Higuchi release, therefore, the release kinetics followed
by zero-order. According to the Korsmeyer-Peppas
model, the value of slope ‘n’ is between 0.94 to 1.71 so
it indicates the diffusion behavior. The formulation F1
indicate that the release mechanism from the films
follows non-Fickian diffusion n=0.94 (0.50 > n > 0.10)
and formulations F3, F7, F9 release mechanism from the
films follows Case II (relaxational) transport obey when
n = 0.10, The remaining formulations F2, F4, F5, F6 and
F8 follows super case II transport (n > 0.10) Table
522,27,36
.
Table 5: In-vitro Drug Release Kinetic Studies of Different
Rivastigmine Buccal Patches.
Formulation
Code
Zero-
order
First-
order
Higuchi Hixon
Crowell
Release
Exponent
(n)
(R2
)
F1 0.959 0.903 0.806 0.927 0.94
F2 0.984 0.912 0.948 0.946 1.324
F3 0.996 0.934 0.994 0.971 1.008
F4 0.987 0.849 0.963 0.919 1.133
F5 0.985 0.884 0.959 0.933 1.321
F6 0.97 0.899 0.935 0.938 1.71
F7 0.946 0.814 0.929 0.876 1.096
F8 0.974 0.832 0.924 0.895 1.258
F9 0.979 0.969 0.992 0.984 1.088
(R2
= Regression Coefficient), (n = Release Exponent).
CONCLUSIONS:
By using rivastigmine as a model drug, buccal films
prepared using various polymers by the method of
solvent casting technique. In the present study, nine
formulations prepared using three polymers in different
ratios, along with plasticizers and penetration enhancers.
Finally, it concluded that the highest drug release
obtained with the film containing sodium alginate and
Eudragit RL100 in combination in formulation F7 which
showed a drug release of 85% at the end of 8 hours.
From the result of in-vitro drug permeation studies, it
found that the release kinetics follow zero-order drug
release except for F9. Accordingly, rivastigmine can be
helpfully managed orally as buccal films with the lesser
event of its side effects and enhanced bioavailability.
ACKNOWLEDGEMENT:
The authors are grateful to Indian Immunological Ltd,
Gachibowli, Hyderabad, India for providing drug
rivastigmine as a gift sample.
CONFLICT OF INTEREST:
The authors have declared no conflict of interest.
AUTHORS CONTRIBUTIONS:
All the authors have contributed equally
STATEMENT OF HUMAN AND ANIMAL
RIGHTS:
With human or animal subjects, this clause does not hold
any studies or performed by any of the authors.
Research J. Pharm. and Tech. 14(10): October 2021
5140
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Development and evaluation of trans buccal patches for Alzheimer's treatment

  • 1. Research J. Pharm. and Tech. 14(10): October 2021 5133 ISSN 0974-3618 (Print) www.rjptonline.org 0974-360X (Online) RESEARCH ARTICLE Development and Evaluation of Trans Buccal Patches based on Natural and Synthetic Polymers Loaded with Rivastigmine using Solvent Casting Technique Prasanta Kumar Mohapatra1 *, Boddu Pavan Kumar2 , Pankaj Singh Patel1 , Harish Chandra Verma1 , Satyajit Sahoo3 1 Moradabad Educational Trust Group of Institutions, Faculty of Pharmacy, Moradabad - 244001, Uttar Pradesh, India. 2 Lydia College of Pharmacy, Ravulapalem - 533238, Andhra Pradesh, India. 3 C. U. Shah College of Pharmacy and Research, Surendranagar - 363001, Gujrat, India. *Corresponding Author E-mail: mohapatra.kjr@gmail.com ABSTRACT: Mucoadhesive buccal films of rivastigmine were prepared by the solvent casting technique using HPMC K15M, sodium alginate, glycerine, and Eudragit RL100. Arranged films assessed for weight variation, thickness, % drug substance, % moisture loss, % moisture take-up, folding endurance, in-vitro medicament release, and Fourier transform Infrared spectroscopy (FTIR). The films showed a controlled release (CR) over 8 h. The preparation observed to be a worthy candidate for the development of buccal patches for therapeutic purposes. Drug-polymer compatibility considers FTIR demonstrated no contradiction between the medicament and the polymers. The optimized formulation found F7 indicated drug release 85% at the end of 8 h. Thinking about the correlation coefficient (R2) values got from the kinetic equations, the drug release from the formulations F1-F8 has discovered zero-order release mechanism. It can be concluded that oral buccal patches of rivastigmine, for treatment of Alzheimer’s and Parkinson’s disease, can be formulated. The study suggests that rivastigmine can be conveniently administered orally in the form of buccal patches, with the lesser occurrence of its side effects and improved bioavailability. KEYWORDS: Buccal Patches, HPMC K15M, Sodium Alginate, Eudragit RL100, Solvent Casting Technique. INTRODUCTION: The drug delivery systems (DDSs) generally comprise tablets, suspension, cream, ointment, liquid, injectable, and aerosol. Today widely used DDSs are conventional DDSs. The methods that apply to get the therapeutic agent in the human body known as drug delivery. The delivery system’s other role is to allow the safe application of the drug. So, in the formulation, the medicament must be physically, synthetically, and microbiologically steady. By the use of suitable DDSs, the side effects of the drug and drug interactions should be minimized or avoided. The convenience of drug administration should be improved by the delivery systems1 . Received on 20.04.2020 Modified on 12.10.2020 Accepted on 19.01.2021 © RJPT All right reserved Research J. Pharm. and Tech. 2021; 14(10):5133-5140. DOI: 10.52711/0974-360X.2021.00894 Any drug delivery system (DDS) attains the release of the drug over a prolonged period known as a sustained- release drug delivery system (SRDDS), which is not time-dependent. In formulating a sustained-release (SR) dosage form hydrophobic polymer matrix commonly used. The character of the ultimate DDS is to provide an accurate site of action to maintain the therapeutic range of drug in blood plasma and to deliver the right amount of medicament at a regular time intermission. The most famous form of controlled release drug delivery system (CRDDS) is an oral CRDDS, and it is the clear advantage of the oral route of drug administration. Such methods release the drug with a steady or fluctuating release rate. A typical pattern of drug release shown by the oral CRDDS, an extended period, and the drug concentration maintained in the therapeutic window. The better control of plasma drug levels, less side effect, fewer dosage frequencies, increased efficacy, and continuous transfer, delivered by CR dosage form2,3,4 . The plasma concentration of drugs within the therapeutic
  • 2. Research J. Pharm. and Tech. 14(10): October 2021 5134 window, for an extended time maintained by CRDDS, to confirm sustained therapeutic action and for that purpose, a growing interest in their growth exists in hypothetical drug concentration profiles, then single doses of immediate-release, SR, and control release drug delivery systems (CRDDSs)5 . The active agents mainly released from a delivery system by three primary mechanisms are diffusion, swelling, and degradation followed by diffusion. When a drug or other active agent permeates through the polymer by a diffusion mechanism that creates the CR device. In the polymer matrix or on a molecular level or by passing between polymer chains on a macroscopic scale as through pores, the diffusion can occur6 . The CRDDSs have created and developed for controlling the rate of drug delivery, targeting the delivery of a drug to tissues, and/or sustaining the duration of therapeutic activity7 . An important route of drug administration has lately discovered is a buccal drug delivery (BDD). For BDD, several bio-adhesive mucosal dosage forms developed, like gels, ointments, adhesive tablets, patches, and more recent film. In the mid-1980's the idea of mucosal adhesive or mucoadhesive introduced into the CRDDS. The adhesive attached to mucosal is natural or synthetic polymers that intermingle with the mucus layer cover up the epithelial surface of mucosal and mucin molecules, which is organizing a major part of the mucus8 . The likelihood that these polymers can be utilized to defeat physiological boundaries to long-term drug delivery, this idea of mucoadhesive has informed by numerous investigators9 . The investigators made the treatment safer and more effective, not only for topical disorders but also for systemic difficulties10 . An Acetylcholinesterase Inhibitor drug rivastigmine inhibits both Acetylcholinesterase and Butyrylcholinesterase (unlike Donepezil, which selectively inhibits Acetylcholinesterase). It is better to work by preventing these cholinesterase enzymes, which would otherwise collapse the brain Neurotransmitter acetylcholine11 . The established treatment effects of rivastigmine have on the cognitive (memory and thinking), functional (activities of daily living) and behavioral problems generally linked with Alzheimer's12,13,14 and Parkinson's disease dementias15 . Orally or via a transdermal patch the drug rivastigmine can be administered; the latter decreases the occurrence of side effects,16 which typically consist of nausea and vomiting17 . The drug rivastigmine is excreted through the urine and performs to have relatively rare drug-drug interactions17 . It is a white to off-white, fine crystalline powder i.e., both hydrophilic (soluble in water) lipophilic (soluble in fats) and it arises in a multiplicity of administrations, including a capsule, solution, and transdermal patches. Comparable to other Cholinesterase Inhibitors17 bio-adhesive patches are used in the mouth, which releases the drug after contact with oral mucosa and absorbs directly by entering into a systemic solution. The patches are commonly prepared by a solvent evaporation technique18 . The objective of this study was to prepare rivastigmine mucoadhesive buccal patches and evaluate their properties. MATERIALS AND METHODS: Materials: Rivastigmine was procured as a gift sample from Indian Immunologicals Ltd, Gachibowli, Hyderabad, India. The Eudragit RL100 and HPMC K15M Purchased from Otto Chemicals and Oxford Chemicals. Sodium alginate, plasticizer, and glycerine procured from Rankem Pvt Ltd, India. All other chemicals are of analytical grade, procured from the authorized dealer19,20,21,22 . Drug-polymer Compatibility: To explore any conceivable collaboration between the medication and the used polymers under scrutiny, FTIR spectrophotometer strategy utilized. In FTIR study the pure drug rivastigmine and a physical blend of pure drug and polymers accomplished on Tensor 27, Bruker Optics, Germany by a KBr dispersion method. The 400 cm-1 to 4000 cm-1 range selected for FTIR spectra (Fig. 3 and 4 )23,24,25,26 . Determination of λ Max of Rivastigmine in 6.8 pH Buffer: The required quantity (100mg) of pure drug rivastigmine dissolved in 6.8 pH to make a solution of 1000µg/ml in a 100ml volumetric flask. By diluting the above solution to 10µg/ml, then the solution scanned between 200- 400nm range to get maximum absorption. From the spectra of drug rivastigmine, maximum absorption 262nm selected for the analysis21,27 . Calibration Curve of Rivastigmine with 6.8 Phosphate Buffer: A stock solution containing 1mg/ml of the pure drug prepared by dissolving 100mg of rivastigmine insufficient 6.8 pH buffer to produce a 100ml solution in a volumetric flask. From the 1000µg/ml standard stock solution, 1ml, 2ml, 3ml, 4ml, 5ml of solution were pipette out into 10ml volumetric flasks. The volume made up to mark with buffer. These dilutions give 100 µg/ml, 200µg/ml, 300µg/ml, 400µg/ml and 500µg/ml concentration of rivastigmine, respectively. The calibration crook fed in the concentration range of 100- 500µg/ml at 262nm. The concentration of the sample solution by using the calibration curve can be determined21,24 . Preparation of Mucoadhesive Buccal Patches: The Solvent casting method employed to prepare buccal patches by using HPMC K15M, Sodium alginate, and Eudragit RL100 as polymers. According to the lot formula, all the ingredients in hold pharmaceutical, polymer, and excipients estimated even.
  • 3. Research J. Pharm. and Tech. 14(10): October 2021 5135 Table 1: Composition of Different Buccal Mucoadhesive Formulations. Compounds F1 F2 F3 F4 F5 F6 F7 F8 F9 Rivastigmine (mg) 70 70 70 70 70 70 70 70 70 Sodium Alginate (mg) 500 * * 750 * * 325 325 * Eudragit RL100 (mg) * 500 * * 750 * 325 * 325 HPMC K15M (mg) * * 500 * * 750 * 325 325 Glycerine (ml) 65 65 65 65 65 65 65 65 65 Methanol (ml) * 20 * * 20 * 20 * 20 Water (ml) Up to 30 ml Up to 30 ml Up to 30 ml Up to 30 ml Up to 30 ml Up to 30 ml Up to 30 ml Up to 30 ml Up to 30 ml Note: * the particular excipient not utilized in the formulation The medicament and all the ingredients have taken on a butter wallpaper with the aid of a stainless-harden spatula than the ingredients dissolved in the water containing measuring glass. After dissolving the drug and polymers completely, plasticizer and permeation enhancer added. Then the complete solution transferred to a petri plate and kept for drying and patches are collected24,28,29 . Statistical design: Most formulation strategy contains the variation of one factor at a time, keeping other factors steady. Such an empirical technique is satisfactory, but when factors are independent of each other. The factorial designs permit all factors to change, in this way permitting evaluation of the impact of every factor at each point and indicating interrelationship among them. A statistical model encompassing interactive and polynomial expressions utilized to evaluate the reactions. A factorial design utilized sequentially to study the outcome of independent formulation variables (amount of sodium alginate, Eudragit RL100, HPMC K15M, and Methanol) specified as factors X1, X2, X3 and X4 on the release profile of rivastigmine from mucoadhesive buccal patches. Table 2 summarizes a record of the nine-formulations examined, their factor combinations, and the coded levels of the experimental units utilized during the study4,34 . Table 2: Experimental Factorial Design Layout. Coded levels Coded factors and their actual values X1 = Sodium alginate (mg) X2 = Eudragit RL100 (mg) X3 = HPMC K15M (mg) X4 = Methanol (ml) -2 * * * 20 -1 325 325 325 * 0 500 500 500 * +1 750 750 750 * Formulation code Coded factors and their levels X1 X2 X3 X4 F1 0 * * * F2 * 0 * -2 F3 * * 0 * F4 +1 * * * F5 * +1 * -2 F6 * * +1 * F7 -1 -1 * -2 F8 -1 * -1 * F9 * -1 -1 -2 Note: * the particular excipient not utilized in the formulation Fig. 1: Photograph of Prepared Mucoadhesive Buccal Patch of Rivastigmine Evaluation of the Transdermal Patches: Physical Appearance: Mucoadhesive buccal patches visually scrutinized for color, flexibility, homogeneity, and smoothness19,30 . Thickness and Weight Variation: By using a thickness gauge, the thickness of the patch at three unalike points determined. To decide the mass of individual patch, the patch separated from the cast patch and the patches weighed independently utilizing a digital balance. The weight variation performed by individually weighing ten randomly selected patches. Same as the test carried out for each formulation24,29,31,32 . Folding Endurance: In the laboratory by designing an apparatus, the folding endurance test for patches (2cm x 2cm) executed. For the folding endurance test, the disintegration mechanical assembly was reworked. For holding the patch, the device comprises two braces. Out of two clamps, one clamp was a constant place while another clamp was moving provision. The movable clamps moved 5cm distance at a speed of 30rpm. The patch will be slightly stretched when the patch was at a maximum distance. Until the patch broke into two pieces, the apparatus allowed to run. By rpm, the folding was counted19,24,29,33,34 . Percentage of Moisture Loss: Accurately gauged patches of every detailing kept at room temperature in a desiccator and presented to a climate having 98% relative humidity (comprise calcium chloride anhydrous) and it weighed following three days. In tripled, the test impelled out. Difference between initial and final weight, the percentage of moisture loss was calculated25,32,33,35 .
  • 4. Research J. Pharm. and Tech. 14(10): October 2021 5136 Percentage Moisture Uptake: In a desiccator accurately gauged patches of every formulation put at room temperature, which kept up at 79.5% relative humidity (saturated solution of aluminum chloride) and following three days gauged. In triplicate, the experiment carried out. Difference between final and initial weight, the percentage of moisture uptake was calculated29,30,36 . Drug Content % Estimation: Patches of the predetermined zone cut, and the pieces transferred into a 100ml volumetric flask comprising phosphate buffer (pH 6.8), and the flask sonicated for 8 h. A blank set up in a similar way utilizing a medicament-free placebo patch of similar dimensions. By utilizing a 0.45μm filter, the solution filtered and the content of the drug analyzed at 262nm by UV-Vis spectrophotometer9,27,34,37,38 . In-vitro Drug Release Studies: The in-vitro release studies impelled out by applying the diffusion mechanism in a glass beaker with the help of a modified magnetic stirrer. The compartment maintained at 37±1°C employing an electric control circulator and also verified manually by using a thermometer. The compartment loaded up with newly arranged phosphate buffer pH 6.8. The solvent in the receptor compartment persistently mixed at 60 rpm utilizing a Teflon covered magnetic stirrer, in command to shun diffusion layer expression. The commercial semi-porous layer mounted between the giver and receptor compartment and verified set up by methods for a brace. The patch set on one side of the semi-penetrable layer. Aliquots of 1 ml were remote from the receptor pigeonhole by methods for a syringe and supplanted promptly with a similar volume of support arrangement kept at 37±1°C. Test samples taken from the medium at predetermined time intervals throughout 8 h the samples analyzed for rivastigmine content by UV-Vis spectrophotometer at 262 nm20,24,28,29 . Kinetics of Drug Release: The diffusion kinetics of the rivastigmine analyzed by a graphical method for zero-order, first-order, Higuchi, Hixon-Crowell, and Peppa’s exponential equation. To study the study kinetics, data obtained from the in-vitro release plotted in various kinetic models4,24,39 . Zero-order Model: From the pharmaceutical dosage forms dissolution of the drug does not disaggregate and release the drug little by little and the graph plotted as % drug released Vs time in ‘h’ can be expressed by Qt = Q0 + k0t (1) Where, Q0 = Initial concentration of drug at time t = 0 Qt = Amount of drug dissolved at a time t K0 = Zero-order constant in concentration/time t = Time in h First-order Model: This model is the necessity to decide the absorption and/or elimination of some drugs, regardless of whether it is hard to conceptualize this mechanism on a hypothetical premise. The diagram was a conspiracy as a log % cumulative drug last Vs time in ‘h’. Log Qt = log Q0 – Kt / 2.303 (2) Where, Qt = Percent of drug remaining at time t Q0 = Initial concentration of drug K = First-order constant t = Time in h Higuchi Model: It is a first mathematical model that defines drug release from a matrix system, recommended by Higuchi in 1961. The intrigue graph drowned % cumulative drug discharged Vs square root of time. Qt = KHt1/2 (3) Where, Qt = Amount of drug released at time t per unit area A KH = Higuchi dissolution constant reflecting design variable system t = Time in h Hixon Crowell Model: The particles that have a uniformed size, the equation derived by Hixson and Crowell describes the dissolution rate based on the weight of the particles cube root and the particle radius not assumed to be variable. It is calculated by the equation, Q0 1/2 - Qt 1/2 = KHt (4) In the pharmaceutical dosage form, the incipient amount of medicament is Q0 and the rest of the measure of medication in the pharmaceutical dosage form is Qt at a time ‘t’ and ‘KH’ is a Hixson-Crowell proportionality consistent. From the acquit kinetics, information acquired from in-vitro medicament release studies plotted as the cube root of % medicament remaining Vs time in ‘h’24,39 . Korsmeyer Peppa’s Model: Mt/ M∞ = K tn (5) Where the quantity of drug release at time t is Mt, and the amount released at a time is M∞ where t =∞, thus Mt / M∞ is the at a time ‘t’ fraction of drug released, the kinetic constant known as ‘k’, and diffusion exponent is ‘n’ and for both solvent penetration and drug release mechanism characterized by the above equation. The correlation coefficient set up by executing the obtained data into various kinetic models. From the slope, the rate constants of respective models calculated. The ‘n’ esteem utilized to portray different releases for mucoadhesive film substances and depicted in Table 5. For the occasion of film, Fickian diffusion relates when
  • 5. Research J. Pharm. and Tech. 14(10): October 2021 5137 n ≤ 0.50 and non-Fickian transport relates 0.50 < n < 0.10, Case II (relaxational) transport obey when n = 0.10, and in case of n > 0.10 obeys super case II transport40,41,42 . RESULTS AND DISCUSSION: Calibration Curve Preparation: Calibration curves of rivastigmine in phosphate buffer pH 6.8 solutions constructed at λ max 262nm with a (Shimadzu Corporation, Kyoto, Japan). Beer’s law obeyed to construct the calibration curve was in the concentration range of 100-500μg/ml. The analysis done in triplicate24 . Table 3: Calibration Curve of Rivastigmine in 6.8 pH Buffer. Concentration (µg/ml) Absorbance (Mean ±SD) 0 0 100 0.133 200 0.272 300 0.41 400 0.545 500 0.678 Fig. 2: Calibration Curve of Rivastigmine in 6.8 pH Buffer Physical Appearance: All the mucoadhesive buccal patches formulated utilizing different concentrations of polymer were achieved transparent, uniform, smooth, flexible, and homogeneous19,30,43 . Thickness Uniformity: All the patches have found uniform thickness. The mucoadhesive buccal film thickness was found between 0.225±1.1 mm to 0.268±1.1 mm24,35,43 . Percentage of Moisture Loss: Precisely weighed patches of all formulation held at room temperature in a desiccator and introduced in an environment of 98% relative dampness (comprising anhydrous calcium chloride) and weighed the following three days. The test moved out in treble. The moisture loss percentage determined by calculating the difference between the initial and final weight concerning initial weight at the dry condition. The achieved values were between 5.10±0.3% to 12.42±0.4%32,35 . Percentage Moisture Uptake: Correctly gauged patches of each formulation placed in a desiccator and which was 79.5% relative moisture, previously mentioned (comprise aluminum chloride saturated solution) at room temperature and following three days similar patches gauged. The test performed in triplicate. When the formulations contain standard moisture content, the film remains stable, non-brittle, and free from complete drying. The optimum standard of moisture absorption found in formulation F1, F4 and F7, so there is less chance of microbial contamination and maintaining integrity in the entire shelf life. The percentage of moisture uptake calculated by initial and final weight and the founded range was 4.64±0.03% to 10.33±0.01% (Table 4)29,35,44 . Folding Endurance: An idea about the flexibility or brittleness of films specified by folding endurance. Good limberness gives high excellence of folding endurance, but fragility films give a less value of folding endurance. All the films didn’t show any crack or cut after over 200 times, folding according to the obtained results, and all were having acceptable flexibility. The results observed in Table 429,35,37 . Weight Variation Test: All the film's weight found to be uniform. The weight found between 99.09±1.1 mg to 100±1.2 mg. It observed from the obtained results that by increasing the polymer concentration the weight of the film also increases. Any deviation in the film's weight leads to under-dosage or overmedication possessed by a momentary feature known as weight variation test. The weight results shown in Table 424,26,35 . Drug Content Percentage: The accurate distribution of the drug ensured by the drug content estimation. For every formulation, the test is done in triplicate, and arise results were ready in Table 4. The results indicate that the drug uniformly dispersed means proper content, uniformity found. The percentage of drug content found between 92.41±0.1% to 98.59±0.6%24,31,38 . Drug-polymer Compatibility: FTIR spectra of pure drug and a mixture of the pure drug and polymers introduced in Fig. 3 and 4. FTIR spectrum of pure drug rivastigmine displays the peaks at 666.79 cm-1 , 902 cm-1 , 1125 cm-1 , 1228.33 cm-1 , 1401.33 cm-1 , and 1691.39 cm-1 . These peaks can be reflected as characteristic peaks of rivastigmine not affected and detected in the FTIR spectra of rivastigmine together with polymers as presented in Fig. 4, which showed that between drug and polymers there was no interaction24 .
  • 6. Research J. Pharm. and Tech. 14(10): October 2021 5138 Table 4: Physicochemical Evaluation Data of Rivastigmine Patches. Formulation Code Appearance Surface Texture % Moisture Loss* % Moisture Uptake* Folding Endurance Thickness (mm)* Weight Variation (mg)* % Drug Content* F1 + VS 9.36 ± 0.6 4.64 ± 0.05 >200 0.248 ± 0.6 99.87 ± 1.4 94.9 ± 1.3 F2 + VS 8.63 ± 0.4 7.25 ± 0.07 >200 0.225 ± 1.1 99.7 ± 1.9 96.5 ± 0.8 F3 + VS 5.75 ± 0.6 6.04 ± 0.04 >200 0.234 ± 0.8 99.09 ± 1.1 94.5 ± 0.9 F4 + VS 9.36 ± 0.7 4.64 ± 0.06 >200 0.268 ± 1.1 99.87 ± 1.4 96.5 ± 0.8 F5 + VS 8.63 ± 0.8 7.25 ± 0.09 >200 0.256 ± 0.9 99.98 ± 1.2 94.9 ± 0.8 F6 + VS 8.96 ± 0.6 6.04 ± 0.05 >200 0.258 ± 0.7 99.5 ± 1.8 94.28 ± 1.5 F7 + VS 12.42 ± 0.4 4.64 ± 0.03 >200 0.248 ± 0.6 99.7 ± 1.9 93.45 ± 0.8 F8 + VS 5.10 ± 0.3 10.33 ± 0.01 >200 0.225 ± 1.1 99.09 ± 1.1 98.59 ± 1.6 F9 + VS 8.76 ± 0.2 8.18 ± 0.04 >200 0.234 ± 0.7 100 ± 1.2 92.41 ± 0.9 *Each Value Represents the Mean ±S.D. (n=3) (VS = Very Smooth) In-vitro Drug Release: The release data of rivastigmine from all the patches given in Fig. 5, 6 and 7. It indicates that the drug release time was highest in combinations of sodium alginate and Eudragit RL100 in F7. At pH 6.8, when contrasted to F1 and F3, the formulation F2, the release rate of the drug is slow, might be because of the existence of Eudragit RL100. The data of the in-vitro release fit into different equations and kinetic models to explain the release kinetics of rivastigmine from these buccal patches. Fig. 3: FTIR Sample for Rivastigmine (Pure Drug) Fig. 4: FTIR Sample for Optimized Formulation The release kinetics of rivastigmine followed a zero- order from the patches F1 to F8. The release rate of the drug in polymers was in this pattern Eudragit RL100 < sodium alginate < HPMC K15M. From this data, it found that the release rate found slower by using Eudragit RL100 than others. Again, the formulations F7, F8 and F9 made by combining of two polymers and compared with formulations having more amount of polymer and it found that a combination of polymers gives a good result means extended-release, hence the
  • 7. Research J. Pharm. and Tech. 14(10): October 2021 5139 mechanism of drug release from the rivastigmine patches followed is dissolution controlled. In the formulations F1 to F9, glycerin used as a permeation enhancer. When compared to all the formulations it indicated by the rivastigmine patches in Fig. 5, F7 released 85% of the drug in 8 h24,28,35 . Fig. 5: In-vitro Drug Release Profile of F1, F4, F7 Rivastigmine Buccal Patches Fig. 6: In-vitro Drug Release Profile of F2, F5, F8 Rivastigmine Buccal Patches Fig. 7: In-vitro Drug Release Profile of F3, F6, F9 Rivastigmine Buccal Patches Kinetics of Drug Release: The drug release data then fitted to mathematical models such as a zero-order, first-order, Higuchi, Hixon-Crowell and Korsmeyer-Peppas model and the coefficients of regression values compared. The regression value of films F1 to F8 follows zero-order and only F9 follows Higuchi release, therefore, the release kinetics followed by zero-order. According to the Korsmeyer-Peppas model, the value of slope ‘n’ is between 0.94 to 1.71 so it indicates the diffusion behavior. The formulation F1 indicate that the release mechanism from the films follows non-Fickian diffusion n=0.94 (0.50 > n > 0.10) and formulations F3, F7, F9 release mechanism from the films follows Case II (relaxational) transport obey when n = 0.10, The remaining formulations F2, F4, F5, F6 and F8 follows super case II transport (n > 0.10) Table 522,27,36 . Table 5: In-vitro Drug Release Kinetic Studies of Different Rivastigmine Buccal Patches. Formulation Code Zero- order First- order Higuchi Hixon Crowell Release Exponent (n) (R2 ) F1 0.959 0.903 0.806 0.927 0.94 F2 0.984 0.912 0.948 0.946 1.324 F3 0.996 0.934 0.994 0.971 1.008 F4 0.987 0.849 0.963 0.919 1.133 F5 0.985 0.884 0.959 0.933 1.321 F6 0.97 0.899 0.935 0.938 1.71 F7 0.946 0.814 0.929 0.876 1.096 F8 0.974 0.832 0.924 0.895 1.258 F9 0.979 0.969 0.992 0.984 1.088 (R2 = Regression Coefficient), (n = Release Exponent). CONCLUSIONS: By using rivastigmine as a model drug, buccal films prepared using various polymers by the method of solvent casting technique. In the present study, nine formulations prepared using three polymers in different ratios, along with plasticizers and penetration enhancers. Finally, it concluded that the highest drug release obtained with the film containing sodium alginate and Eudragit RL100 in combination in formulation F7 which showed a drug release of 85% at the end of 8 hours. From the result of in-vitro drug permeation studies, it found that the release kinetics follow zero-order drug release except for F9. Accordingly, rivastigmine can be helpfully managed orally as buccal films with the lesser event of its side effects and enhanced bioavailability. ACKNOWLEDGEMENT: The authors are grateful to Indian Immunological Ltd, Gachibowli, Hyderabad, India for providing drug rivastigmine as a gift sample. CONFLICT OF INTEREST: The authors have declared no conflict of interest. AUTHORS CONTRIBUTIONS: All the authors have contributed equally STATEMENT OF HUMAN AND ANIMAL RIGHTS: With human or animal subjects, this clause does not hold any studies or performed by any of the authors.
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