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An Innovative Mucoadhesive Thermosensitive In situ Gelling Liquid Suppository

of Metoclopramide Hydrocloride for Treatment of Nausea and Vomiting
Associated with Diseases

Article  in  Indian Journal of Pharmaceutical Sciences · November 2020

DOI: 10.36468/pharmaceutical-sciences.691

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 Research Paper
An Innovative Mucoadhesive Thermosensitive In
situ Gelling Liquid Suppository of Metoclopramide
Hydrocloride for Treatment of Nausea and Vomiting
Associated with Diseases
Z. D. SALMAN, A.T. ALHAMDANY* AND N. Z. YOUSIF

Department of Pharmaceutics, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq

Salman et al.: Mucoadhesive Thermosensitive In situ Gelling Liquid Suppository of Metoclopramide HCl

The main purpose of presently study was to formulate and evaluate a controlled release thermogelling
mucoadhesive system of Metoclopramide Hydrocloride given for emetic patients as an alternative for
conventional oral dosage forms. Twelve formulations were prepared by the addition of mucoadhesive
polymers (Hydroxypropyl methylcellulose K15M and Hydroxypropyl methylcellulose K100M, carbopol
934p, and sodium alginate) to the formulations of the thermosensitive gelling solutions containing poloxamer
407 and poloxamer P188. Each of the eleven formulations containing metoclopramide Hydrocloride as an
active drug was evaluated for pH, clarity, drug content, gelation temperature, gel strength, mucoadhesive
force and viscosity. While the succeeded in situ gelling liquid suppository, formulations were evaluated for
spreadability, syringeability, the in vitro release profile of the drug and kinetic studies. Also, the optimum
formulation was evaluated and identified for drug-excipients compatibility study using Fourier transform
infrared spectroscopy. From the characterization of Metoclopramide Hydrocloride in situ gelling liquid
suppositories, it was revealed that the optimized formulation (F4) displayed the best syringeability time
(7.5±0.77 s) that is confirmed by viscosity measurement (335±0.15 cp at 25˚ and 27 470±0.09 cp at 37˚) with
a suitable pH determination (7.01±0.90). While gelation temperature at (37±0.04°) was established with
a spreadability measurement (17.5±0.02 g cm/s). Moreover, adhesiveness at the administration site was
assured by both mucoadhesive and gel strength studies that were realized to be (20.90±0.83 dyne/cm2.100)
and (17.5±0.34 N/m2), respectively. Whereas the drug release method was affirmed through in vitro drug
release profile that shows good control of the release, reaching 97.5 % after 3 h with an appropriate content
uniformity at (98.19±0.0011). The kinetic test of the release data was founded to obey both diffusion and
erosion mechanisms, as the correlation coefficient (R2) was best fitted with the Korsmeyer-Peppas model
and release exponent (n) shown to be between 0.5-1 that was (0.5190). Put together, our results concluded
that thermosensitive liquid in-situ gelling suppositories of Metoclopramide Hydrocloride were effective,
potential, and more convenient alternative for a conventional oral dosage form that was given for emetic
patients; thereby improving patient compliance and medication adherencet.
Key words: Metoclopramide Hydrocloride, Liquid suppository, Thermosensitive in situ gel, HPMC K15M,
Poloxamer 407, Poloxamer 188

The conventional suppository is a traditional favorable by the patients, thus, lowering a patient’s compliance.
rectal dosage form for children and non-cooperating However, these problems can be resolved using
patients. Besides, an ideal suppository should be applied in situ gelling, bio adhesive, and liquid suppositories[2].
without any pain and remain at the administered sites
to avoid the first-pass effect in the liver, therefore, the This is an open access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 3.0 License, which
bioavailability can be increased[1]. One of the major allows others to remix, tweak, and build upon the work non-commercially,
drawbacks of suppositories is the leakage from the as long as the author is credited and the new creations are licensed under
the identical terms
site of action as they melt in the cavities. Moreover,
these routes have a feeling of discomfort and refusal Accepted 02 July 2020
Revised 17 June 2020
Received 03 January 2020
*Address for correspondence
Indian J Pharm Sci 2020;82(4):650-664
E-mail: [email protected]
June-July 2020 Indian Journal of Pharmaceutical Sciences 650
 www.ijpsonline.com
The liquid suppository exists as a solution at room compliance. Therefore, controlled release dosage forms
temperature, so, it can be administered easily with a have the advantages of decreasing side effects, reducing
suitable applicator but at body temperature, it instantly dosing frequency, reducing fluctuations in circulating
gels in the rectum and adheres to the mucous membrane. drug levels, and achieving a prolonged therapeutic
An important eligibility criterion of the system is the effect by continuously releasing medication over an
suitable bioadhesivity so as not to be leaked out from extended period after[9,10]. Moreover, rectal delivery
the anus after administration[3]. seems to be an attractive alternative.
Several attempts have been developed using a This study aims to formulate a controlled release
temperature-sensitive and mucoadhesive liquid thermogelling mucoadhesive system of metoclopramide
suppository through functioning numerous polymers HCl as an alternative for conventional oral dosage
such as poloxamer 188 (P188) and poloxamer 407 forms given for emetic patients that results in improving
(P407), Hydroxypropyl methylcellulose K15M patient’s compliance and medication adherence, also,
(HPMC K15M) and Hydroxypropyl methylcellulose those developed liquid suppositories help to avoid the
K100M (HPMC K100M), carbopol 932, and sodium liver’s first-pass metabolism suggesting an improvement
alginate respectively. As a base of liquid suppositories, in the bioavailability of the absorbed drug.
poloxamer, a nontoxic copolymer of poly (oxyethylene)-
MATERIALS AND METHODS
poly (oxypropylene)-poly (oxyethylene) was used.
These systems are liquids before minimal invasive Materials:
administration into the body. The temperature change
act as a stimulus to show the sol-gel transition of Metoclopramide HCl was purchased from (Provizer
poloxamer[4]. Furthermore, the bioadhesive polymers Pharma, India), sodium alginate was obtained from
like carbopol 934p and sodium alginate have a (Avonchem, UK), poloxamer (188, 407) was supplied
proper attribute to control the gel strength and the from (Baoji Guokang Bio-Technology, China),
bioadhesive force of a liquid suppository[5]. While carbopol (934P) came from (Provizer Pharma, India),
water-soluble HPMC K15M and K100M were used and HPMC (K15M, K100M) was purchased from
as a thermoresponsive base of the liquid suppository. (Gainland chemical company, UK). All other materials
These cellulose derivatives are nonionic water-soluble used were of pharmaceutical grade.
polymers, which can be used as a gel and film-forming
Preparation of poloxamer-HPMC based liquid
agent. On heating the aqueous solution of HPMC K15M
suppository:
and K100M to a certain temperature (Tt), reversible
thermal gelation can be observed. The background of In this preparation, a procedure was adopted ‘‘cold
thermal gelation is the association between the high method’’ to formulate poloxamer-HPMC based liquid
substituted parts and the coverage of hydrophobic suppository as shown in (Table 1). The required amounts
molecule parts in the network of the polymer chain[6]. of poloxamer (407 and 188) for each formulation were
carefully weighed in a 100 ml beaker and dispersed in
Metoclopramide Hydrochloride (HCl) is a potent and
an appropriate volume of distilled water. Subsequently,
popular antiemetic, effective in the treatment of nausea
the beaker was placed inside an ice bath (4°) on a
and vomiting induced by cancer therapy, pregnancy,
magnetic stirrer under continuous agitation for 30
migraine, and radiation sickness. It is rapidly absorbed
min until a homogenized mixture was gained. The
and eliminated after oral administration. Yet, the oral
dispersion was then stored in a refrigerator overnight
bioavailability of metoclopramide HCl is highly variable,
to get a clear solution. The required amount of HPMC
showing values between 32-98 % due to extensive (K15M and K100M) was continuously mixed with 20-
pre-systemic metabolism[7]. The administration of 30 % of the desired volume of distilled water (70°) on a
metoclopramide HCl is usually in a dose of 10 to 20 heated magnetic stirrer. The remaining volume of cold
mg four times daily. Oral forms of this drug often get water was then added to the opaque mixture and stirred
vomited out before systemic absorption. In long term until it cleared up[11,12]. Afterward, both poloxamer and
therapy, fluctuation in the plasma concentration, with HPMC solutions were mixed continuously inside an
high concentration peaks are common for this type of ice bath at 4° on a magnetic stirrer. To this mixture,
drug that has rapid absorption and elimination when metoclopramide HCl and distilled water were added
administered in conventional immediate release dosage up to 80 ml with constant mixing then, stored in a
forms[8]. The oral administration results in low patient refrigerator until use.
651 Indian Journal of Pharmaceutical Sciences June-July 2020
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Preparation of poloxamer-carbopol based liquid appearance of the prepared in situ gelling liquid
suppository: suppository formulations was determined by visual
inspection for color, homogeneity, and clarity under the
Mucoadhesive polymer, carbopol 934P, was dissolved
black and white background[15].
in distilled water by agitation at room temperature.
After that, a cooled poloxamer (188 and 407) solution Drug Content:
(4°) was added slowly, with agitation as shown in
(Table 1). The mixture was then kept overnight at 4° Five ml of the solution was pipetted and dissolved in
until a viscous and clear solution was obtained. To this about 100 ml phosphate buffer (pH 7.4) in a 250 ml
successive solution, metoclopramide HCl and distilled volumetric flask. One milliliter was taken and diluted
water were added up to 80 ml with constant mixing to 10 ml. After shaking for 2 min, the solution was
using a magnetic stirrer and inside an ice bath (4°), filtered through 0.45 µm pore size Millipore filter,
thereafter, stored in a refrigerator until use[13]. and the absorbance of this solution was recorded at
273 nm against phosphate buffer (pH 7.4) as a blank
Preparation of poloxamer-alginate based liquid using ultraviolet (UV)/visible spectrophotometer
suppository: (Shimadzu 1800, Japan). Drug content studies were
In the case of sodium alginate, it was dissolved primarily carried out in triplicate. The concentration of the
in the deionized water at 90° for 10 min and cooled to drug present in the in situ gelling liquid suppository
room temperature. Later, a cooled poloxamer (188 and formulation was calculated from the equation obtained
407) solution (4°) was added slowly, with continuous from the calibration curve[16].
agitation on a magnetic stirrer and inside an ice bath
until a clear solution was acquired. Metoclopramide Measurement of gelation temperature:
HCl and distilled water up to 80 ml were then added
Gelation temperature measurement was performed
to the prepared formulation, subsequently, the solution
was stored in a refrigerator until use[14]. The composition using a procedure reported by Lena Murad Thomas
of the formulation was shown in (Table 1). et al[17]. A 25 ml transparent beaker containing a
magnetic bar and 10 ml of the in situ gelling liquid
Characterization of metoclopramide HCl in situ suppository formulation was placed on a magnetic
gelling liquid suppository: stirrer (DragonLab MS-H-PRO, USA). A digital
thermometer was immersed in the in situ gelling
Determination of pH and general appearance: liquid suppository formulation. The formulation was
The pH of the prepared in situ gelling liquid suppository heated at a constant rate (1°/min) with constant stirring
formulations was determined using a calibrated pH (200 rpm). The gelation temperature was determined
meter (WTW-INO LAB- Switzerland). Determinations as the temperature registered on the thermometer when
were carried out three times then the average was taken the magnetic bar stopped moving due to gelation[18].
as the pH of the prepared formulations. The general Each sample was measured triplicate.

TABLE 1: COMPOSITION OF METOCLOPRAMIDE HCl LIQUID BASED SUPPOSITORY

Metoclopramide HPMC K15M HPMC K100M Carbopol 934p Sodium
Formulations P407 (g) P188 (g)
HCl (mg)/5 ml (g) (g) (g) alginate (g)
F1 10.5 7.5 2.5 0.750 - - -
F2 10.5 10 2.5 0.750 - - -
F3 10.5 12.5 2.5 0.750 - - -
F4 10.5 15 2.5 0.750 - - -
F5 10.5 15 5 0.750 - - -
F6 10.5 15 7.5 0.750 - - -
F7 10.5 15 2.5 1.5 - - -
F8 10.5 15 2.5 0.375 - - -
F9 10.5 15 2.5 - 0.750 - -
F10 10.5 15 2.5 - - 0.750 -
F11 10.5 15 2.5 - - - 0.750
F12 - 15 2.5 0.750 - - -
Metoclopramide HCl (mg)/5 ml: represents 10.5 mg in each dose thus in 80 ml equal to 168 mg, P407: poloxamer 407, P188: poloxamer 188,
HPMC K15M, K100M: hydroxypropyl methylcellulose (K15M, K100M)
June-July 2020 Indian Journal of Pharmaceutical Sciences 652
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Measurement of gel strength: Viscosity measurements of the liquid suppository:

One of the required evaluations of the in situ gelling liquid The viscosity of in situ gelling liquid suppositories
suppositories was the measurement of gel strength. The was affirmed using a Brookfield digital viscometer
in situ gelling liquid suppository formulation (50 ml) (LVDV-E, USA). A 15 ml sample of each formulation
was put in a 100 ml graduated cylinder and placed in a was placed in a glass container. Primarily, viscosity
water bath for 30 min at 37±0.5° to make the solution measurement was recorded at 25±1°, and then the
gel. The gel strength was measured by using the temperature was elevated to reach at 37±0.5° by a
procedure reported by H.-R. Lin et al [19]. An apparatus water jacket through which water was circulated at
having an appropriate perforated size disc (30 g) was 37±0.5° from a thermostat bath. For the determination
placed on top of the in-situ gelling liquid suppositories of viscosity values, a spindle with the number 63 and
in the cylinder. The time required for the disc to move rotating speed of 50 rpm was used for measurements at
5 cm down the cylinder and through the gelled base was 25±1°, while a spindle with the number 64 and rotating
determined. Meanwhile, various weights were placed speed of 50 rpm was used for the measurements at
at the free end of the apparatus where a lightweight pan 37±0.5°[21]. All measurements were performed in
(5 g) is attached in case that it took more than 5 min triplicate and the mean value was calculated.
to drop the apparatus into the gel. Therefore, the gel
strength was described by the least weights that pushed Measurement of spreadability for liquid
the apparatus 5 cm down through the gel. suppositories:

Measurement of mucoadhesive force: For measuring spreadability, a specially fabricated

laboratory apparatus was suitably modified and utilized
Eleven in situ gelling liquid suppositories were for the study. The glass slides were maintained at a
evaluated for the mucoadhesive force using a modified constant temperature of 37° by a hot plate magnetic
balance according to the preceding declared method[20]. stirrer. 2 ml of in situ gelling liquid suppository was
A section of sheep rectal tissues was cut and promptly applied within a circle of 1 cm diameter pre-marked on
held with mucosal side out onto two glass vials using a ground rectangular glass plate over which a second
a rubber band. The exposed diameter of each mucosal rectangular glass plate was placed. The two plates were
membrane was 15 mm. The vials containing the rectal compressed to uniform thickness under tension by
tissues on their ends were preserved at 37±0.5° for placing (500 g) weight on the top plate for 5 min to
10 min before measuring the mucoadhesive force. One expel air and to provide a uniform film of the in situ
vial with a section of tissue was joined to the balance gelling liquid suppositories between the plates. The
instead of one of the pans by a height-adjustable hook, top plate (provided with a hook) was then exposed to
and the other vial was set with (0.15 g) gel spread on it a pull of 50 g with the aid of a string tied with a hook.
and its height altered so that the gel could contact with Spreadability was measured depending on the time in
the mucosal tissues of both vials and was permitted to sec in which the top plate slips off from in situ gelling
adhere for 3 min (preload time). liquid suppositories before getting gelled and as shown
in (fig. 1). The increment in diameter was noted owing to
On the other side of the balance, a plastic cup to collect
the spreading of the in situ gelling liquid suppositories.
water was placed. Water was added drop by drop to the
A shorter interval shows preferable spreadability and an
plastic cup until the weight of water in the cup detached
average of three obtained readings were recorded [22].
the two surfaces from each other. The mucoadhesive
The calculation of spreadability (S) is as the following:
force of the liquid suppository per unit area (F),
expressed as the detachment stress (dyne/cm²), was S= (expressed in g cm sec-1 (gram centimeter/sec)
determined from the minimal weight of water that
Where, M=Weight tide to upper slide (g), L=Length
detached the two vials and was calculated using the
moved on the glass slide (cm), T=Time taken.
following equation: F = 0.98 m/πr2
Measurement of syringeability for liquid
where m represents the weight (g) of water required
suppositories
for detachment, and r represents the radius (mm) of
the mucosal membrane. Measurements were repeated The syringeability of the in situ gelling liquid
triplicate for each of the in situ gelling liquid suppository suppositories was evaluated with a fabricated laboratory
formulations. The rectal mucosal tissue was replaced device. This device was composed of vertical support
for each measurement. (clamp) for a 5 ml plastic Luer lock syringe filled with
653 Indian Journal of Pharmaceutical Sciences June-July 2020
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Higuchi models to establish the release kinetics and
mechanism of drug release. Based on the correlation
coefficient (R2) value in various models, the model that
gives the highest (R2) value is deemed as the best fit of
the release model. Moreover, when the mechanism of
release of metoclopramide HCl from liquid suppository
is not well known, the first 60 % drug release data
were fitted in Korsmeyer-Peppas equation: Mt/M0=Ktn.
Where M0 is the initial amount of drug released at zero
time, Mt is the amount of drug released at time t, Mt/
Fig. 1: Illustrated diagram of fabricated laboratory apparatus M0 is the fraction of drug released at time t, K is a
used for measuring spreadability release characteristic constant of the suppository and n
A: weight 500 g, B: top rectangular glass plate, C: ground is a release exponent related to the mechanism of the
rectangular glass plate, D: 2 ml in situ gelling liquid suppositories,
E: weight 50 g. drug release. As the k value becomes higher, the drug
is released faster. The n =1 corresponds to zero-order
in situ gelling liquid. A second clamp for grasping release if possible, if “n”>1, a super Case II transport
a hollow holder and a weight (1000 g) moving is operative, if 0.5<n<1 it suggest anomalous transport
downwards until it came in contact with the piston to (non-Fickian) release model due to both drug diffusion
support a constant force of 0.5 N on the piston syringe and polymer chain relaxation, and for n≤0.5 indicate
as shown in (fig. 2). A 23G.11/4 inches needle was fixed Fickian diffusion (Higuchi’s model)[26, 27].
on the syringe which was positioned in the support.
Statistical Analysis:
The time necessary for the in situ gelling liquid to be
expelled from the syringe was measured[23]. The tests Statistical analysis was accomplished using Microsoft
were conducted at room temperature 25º and each Excel 2016 software. The results obtained for the
experiment was carried out three times. drug release were reported as means±standard
deviations [SD] (n=3). Differences in parameters from
In vitro release from liquid suppository:
formulations were statistically analyzed by one-way
The release experiment studies of metoclopramide HCl analysis of variance (ANOVA) at a 95 % confidence
from in situ gelling liquid suppository formulations interval. Statistically significant differences were
were monitored using the in vitro dialyzing method defined as p<0.05[28].
in which 5 ml of the prepared liquid suppository
Drug-excipients interaction study and identification:
formulation was syringed into a glass container closed
at one end and the open end covered by a 1.8 cm cap Fourier transform infrared spectroscopy (FT-IR):
in diameter of a hydrophilic membrane of regenerated The FT-IR spectra of pure drug, polymers (poloxamer
cellulose millipore 0.45 μ (soaked for 1 h. before the 407,188 and HPMC K15M), and the drug with the
test in the phosphate buffer), and heated for 10 min to
gelate completely[24]. This glass apparatus was fixed on
the paddle with threads to prevent leakage, on type II
dissolution apparatus (PHARMA TEST DFC-820SP,
Germany) and the release medium 500 ml phosphate
buffer (pH 7.4) was used as a dissolution medium
pre-equilibrated at 37°, throughout 4 h and stirred
at 100 rpm. 5 ml samples were withdrawn at regular
time intervals and replaced with the same volume of
fresh dissolution medium. The samples were analyzed
spectrophotometrically at λmax 273 nm using a UV/
visible spectrophotometer (Shimadzu 1800, Japan)[25].
Each experiment was performed in triplicate.
Fig. 2: Illustrated diagram of fabricated laboratory apparatus
Kinetic evaluations: used for measuring syringeability
A: weight 1000 g, B: hollow holder to grasp the weight, C:
The results of dissolution rate data obtained were
syringe filled with 5 ml in situ gelling liquid suppositories, D:
evaluated kinetically by zero-order, first-order, and double clamp with rack.
June-July 2020 Indian Journal of Pharmaceutical Sciences 654
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polymer (after the in-situ gelling liquid suppository showed that neither P407 nor P188 alone could provide
formed as a gel at 37±0.5°, the formulation was permitted gelation at the physiological temperature. Using
to dry in the air) were recorded on a spectrophotometer a combination of two poloxamer grades, gelation
(Shimadzu 8400S, Japan) using the potassium bromide temperature could be modulated to the desired range[4].
(KBr) pellet technique and spectra was recorded in the The temperature-dependent gelation of poloxamer
transmittance mode with 25 scans acquired at 2 cm-1 solutions could be explained to be due to the desolvation
resolution, between 4000 and 450 cm-1. The spectra of hydrophilic chains of the polymer as a result of
FT-IR records the existence and identification of the the breakage of the hydrogen bonds that have been
functional groups in the formulations. FT-IR spectra established between the solvent and these chains. This
were obtained to investigate any physicochemical phenomenon favors hydrophobic interaction among the
incompatibility interaction between the pure drug and hydrophobic chains of the polymer and the polymer
different excipients in the prepared formulations[29]. self-assemble spontaneously, forming micelles[31].
RESULTS AND DISCUSSION The increment in P407 concentration in formulations
(F1-F4) resulted in lower gelation temperatures; this
Characterization of the in-situ gelling liquid suppository
could be elucidated by the increase in the quantity of
system is a major issue to be considered in the
micelles formation and increased the possibility of
formulation stage, especially those intended for rectal
micelle entanglement and packing with each other[32].
administration.
Formulations (F4-F6) show the effect of P188
The clarity of the formulated in situ gelling liquid
concentration on gelation temperature, the increment of
suppositories was found to be transparent at room
P188 concentration was accompanied by an increase in
temperature with a smooth and homogenous
the gelation temperature of formulations. A conceivable
appearance. Generally, the properties of rheological
reason for this is due to the small amount of P188
fluids can be influenced by the pH of the dispersion
medium, because it can change the gelation process and incorporated compared to the amount of P407 which
the gel structure. In our study, the pH of prepared liquid only resulted in changing the poly-ethylene oxide/ poly-
suppositories is shown in (Table 2). They were found to propylene oxide (PEO/PPO) ratio and an increment in
be in the range of 7.01–7.44; this range is considered to gelation temperature without affecting the micellization
be close to the pH of the rectum and is an indication of process and participation of P188 molecules in the
the suitability for rectal application with minimal risk construction of the gel[33].
of tissue irritation[17]. It was observed that gelation temperature depends on
The determined drug content values were ranged the type and concentration of mucoadhesive polymer
from 98.29 to 101.00 as shown in (Table 2) and this used in the formulation. All studied mucoadhesive
indicates homogeneity of the drug in the in situ gelling polymers lowered the gelation temperature; the results
liquid suppository formulations. The difference in drug showed that increasing the concentration of HPMC
content from different formulations may be due to their K15M (F8, F4, and F7) produced a significant (p<0.05)
different pH and electrolyte in their formulations[27,30]. decrease gelation temperature of the corresponding
liquid suppositories as shown in (Table 2)[20]. Moreover,
Gelation temperature measurement was performed in
formulations (F9, F10, and F11) prepared by the
this study due to a remarkable property that should exist
addition of HPMC K100M, carbopol 934p, and sodium
in the in situ gelling liquid suppositories when given to
alginate respectively, as mucoadhesive polymers to the
the patients; which is the transition of the liquid phase to
in situ gelling liquid suppository preparations instead
a gel when temperature varied. It has been notified that
of adding HPMC K15M in the formulation (F4). It was
an acceptable in situ gelling liquid suppository should
noted that the gelation temperature became lower (36,
possess a gelation temperature between 30 and 37°, to
34, and 33˚), respectively, as shown in (Table 2). This was
be in a liquid form at room temperature, and capable to
attributed to their ability to bind to the polyoxyethylene
form a gel phase immediately in the rectum[13].
chains present in the poloxamer molecules. This
Poloxamer solutions were recognized to show will promote dehydration, causing an increase in an
thermoreversible, temperature-dependent gelation, entanglement of adjacent molecules and extensively
based on the polymer grade, concentration, and other increasing intermolecular hydrogen bonding, which
involved formulation components. Preceding findings will lead to gelation at a lower temperature[34,35].
655 Indian Journal of Pharmaceutical Sciences June-July 2020
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TABLE 2: PHYSICOCHEMICAL PROPERTIES OF METOCLOPRAMIDE HCl IN SITU GELLING LIQUID
SUPPOSITORIES
Drug Content Gelation Gel Strength Mucoadhesive Force
Formulations pH
(%) temperature (˚) (N/m2) (dyne/cm2) • 100
F1 7.35±0.11 98.57±0.0031 52±0.14 11.1±0.02 15.89±2.04
F2 7.23±0.09 102.76±0.002 50±0.07 14.2±0.12 16.73±0.73
F3 7.12±0.14 93.23±0.0013 45±0.11 16.4±0.22 18.82±1.76
F4 7.01±0.90 98.19±0.0011 37±0.04 17.5±0.34 20.90±0.83
F5 7.06±0.10 96.98±0.0034 58±0.09 19.6±0.06 23.01±0.55
F6 7.1±0.80 100.12±0.0032 62±0.12 22.4±0.17 26.12±1.62
F7 7.08±0.24 102.89±0.0021 32±0.05 13.2±0.45 22.84±1.06
F8 7.13±0.03 98.28±0.0014 38±0.16 9.8±0.33 14.33±0.98
F9 7.25±0.33 99.96±0.0024 36±0.21 15.3±0.42 24.72±1.50
F10 6.82±0.34 100.78±0.0027 34±0.03 13.6±0.33 32.21±0.97
F11 7.44±0.21 101.86±0.0038 33±0.31 10.9±0.16 56.44±0.46
F12 7.11±0.23 ------------- 35±0.17 15.3±0.23 10.23±0.63
Data were given in mean±SD, n=3

Since metoclopramide HCl is the active material of Nevertheless, the effect of P188 on gelation (sol-gel
the prepared in situ gelling liquid suppository (F4), transition) was found to be more noticeable than on
thus its effect on the physicochemical characteristics micellization. This is probably because their effects on
of these suppositories should be studied. During the poly-ethylene oxide (PEO) chains are more important
experiments, the amount of metoclopramide HCl than their effects on poly-propylene oxide (PPO) cores.
incorporated in these rectal dosage forms was found to It is generally accepted that the monitor of micellization
increase the gelation temperature on the contrary to the is the dehydration of the PPO block, and that once
formulation prepared without using active ingredient the micelles formed; the rearrangement of micelles
(F12) as shown in (Table 2). This is maybe associated depends on the interaction between the hydroxylic
with the fact that these water-soluble substances cause groups. It is reasonable to suppose that the presence
modification of the process of micellar association of of P188 may disturb the formation of hydrogen bonds
poloxamer solutions leading to an increase in gelation between the micelles of P407, in which case the gelation
temperature[26]. becomes more difficult, and thus gelation temperature
increases[37].
Gel strength measurement of the in situ gelling liquid
suppository is considered as an important signal for the Also, gel strength measurement was likewise conducted
for in situ gelling liquid suppository formulations
viscosity of the solution at physiological temperature.
after incorporation of a mucoadhesive polymer
Therefore, it is deemed as a vital parameter in the
(HPMC K15M) for comparative evaluation (F8, F4,
development of in situ gelling rectal suppositories, thus,
and F7) as shown in (Table 2). It may reveal that the
to find the suitable condition of moderate gel strength
addition of HPMC K15M increased the gel strength of
which allows the easy insertion of these in situ liquid
formulations significantly (p<0.05) in a concentration-
suppositories and prevents their leakage from the anus
dependent technique. The mechanism of increment
after insertion when the gel strength is low.
might be associated with hydrogen bonding between
Gel strength was affected by the concentration of poloxamer and the mucoadhesive polymer in the rectal
poloxamer used. Increasing the concentration of P407 gel[38]. Moreover, a decreasing order in the gel strength
(F1-F4) resulted in a significant (p<0.05) increase in the values was observed (Table 2) after the addition of
gel strength. This could be a result of the enlargement of mucoadhesive polymers [HPMC K100M (F9), carbopol
micelles and tight packing of adjacent micelles leading 934p (F10), and sodium alginate (F11)] as an alternative
to gel formation at lower temperatures. The gel is more of adding HPMC K15M (F4). This might be assigned
entangled at a higher concentration of P407[36]. In the to that, the polymer with hydrophilic groups as the
case of P188, increasing the concentration of liquid carboxyl and hydroxyl groups can be bind strongly to
suppository F4-F6 was accompanied by shifts in both the oligosaccharide chains by firming hydrogen bonds,
micellization and gelation (micelle rearrangement). electrostatic attraction, or hydrophobic interaction[39].
June-July 2020 Indian Journal of Pharmaceutical Sciences 656
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Furthermore, incorporation of metoclopramide HCl polymers that increase hydrogen bonding between the
into in situ gelling liquid suppositories (F4) could gel formulation and mucosal membrane[45-47].
increase the gel strength. Otherwise, formulation (F12)
The incorporation of metoclopramide HCl into
displays a less gel strength when the drug was not
poloxamer gel (F4) increased the mucoadhesive force
incorporated into it as shown in (Table 2). A possible
as compared to (F12) where the drug was not added
mechanism by which metoclopramide HCl affected the
and as shown in (Table 2). This can be elucidated by
gel strength was speculated to be due to the hydrophilic
the increase in water uptake into the gel matrix due to
nature (water-soluble) of the drug that could bind
the amalgamation of metoclopramide HCl leading to
strongly with the cross-linked reticular structure of the
facilitate the interaction between the polymer and mucus
poloxamer gel[40].
and thus producing higher mucoadhesive strength[48].
Mucoadhesive measurement is an important parameter
The viscosity of in situ gelling liquid suppositories
to be measured for rectal formulations including
affected the drug release rate and the distribution in
in situ gelling liquid suppositories. This physicochemical
the distal portion of the large intestine. Furthermore,
property indicates the bioadhesive force needed
the relative viscosity might offer some insight into the
to prevent gelled suppositories from reaching the
predictable retention time and mucoadhesive strength
upper part of the rectum where the first-pass effect is
of the gel. Additionally, the rheological properties
probable. Also, liquid suppositories must have suitable
evaluation of the formulation as a dosage form would
bioadhesive strength meanwhile if the bioadhesive force
be vital for expecting their behavior in vivo[27]. The
is too excessive, the gel can damage the rectal mucous
viscosity of the in situ gelling liquid suppositories
membrane. Whereas if bioadhesive force is inadequate
in the tested experimental conditions as shown in
then rapid leakage will occur and the retention time in
(Table 3).
the rectum will decrease[41].
The effect of temperature on viscosity of metoclopramide
In the current study, as shown in (Table 2), the
HCl in situ gelling liquid suppositories at 25˚ was
mucoadhesive force was affected by the concentration
established on all formulation solutions (F1-F12)
of poloxamer used. Primarily, the mucoadhesive force
and shown in (Table 3). It was confirmed that these
was increased with the increment in P407 concentration.
formulations were in liquid form at room temperature
Chain entanglement and physical interlinking interaction
with low viscosity and exhibited a Newtonian behavior.
of the P407 with the mucous membrane could be the
Therefore, to ensure an easy administration and a
main reason for this highly effective mucoadhesion[42,43].
homogeneous spreading of the formulation on the
Then, the effect of adding P188 to the in situ gelling
mucosa[49].
liquid suppositories, which is homologous of P407,
was found to enhance mucoadhesive force. This may At 37˚, the behavior of P407 solutions changed,
be due to the binding of the hydrophilic oxide group depending on the amount of polymer used. As the
of poloxamer to the oligosaccharide chains. Thus,
the higher the concentration of P188, the greater the TABLE 3: VISCOELASTIC PROPERTIES OF
mucoadhesive force of poloxamer gels[44]. METOCLOPRAMIDE HCl IN SITU GELLING LIQUID
SUPPOSITORIES
Moreover, increment in the concentration of different Viscosity (Cp)
RPM 5
mucoadhesive polymers (F9-F11) results in an increase Formulations
At 25˚ At 37˚
of the mucoadhesive force as compared to (F4) as
F1 197±0.34 12630±0.14
shown in (Table 2). This may be due to increasing
F2 226±0.56 18540±0.74
the bond-forming groups and more adhesive sites at F3 284±0.62 21230±0.41
the polymer chains for interpenetration with mucin, F4 335±0.15 27470±0.09
resulting accordingly in an increase in mucoadhesive F5 397±0.24 28370±0.13
strength. The mucoadhesive polymers can be arranged F6 410±0.46 30120±0.38
according to their mucoadhesive force enhancing F7 468±0.04 38880±0.14
effect at 0.75 gm of liquid suppositories as sodium F8 266±0.51 23750±0.52
alginate>carbopol 934p>HPMC K100M. The F9 440±0.22 39420±0.67
F10 420±0.77 37550±0.65
mechanism of the mucoadhesion may be related to
F11 380±0.35 31360±0.56
the abundance of secondary bond-forming groups
F12 350±0.11 27160±0.21
(e.g. hydroxyl, carboxyl, and ether groups) in these Data were given in mean±SD, n=3
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amount of P407 in the prepared in situ gelling liquid that the solution turns out to be immobile and gel is
suppositories increased (F1-F4), the apparent viscosity created. Additionally, the conformational modifications
increased with an increase in gelation properties in the orientation of the methyl groups in the side chains
which confirmed the (pseudoplastic) behavior of poly (oxypropylene) polymer chains, establishing the
(Table 3). Besides, it is well recognized that core of the micelle, with the removal of the hydrating
poloxamers are amphiphilic polymers and display a water from the micelles will participate to the gelation
thermo-reversible performance in aqueous solution phenomenon[54]. While comparing these formulations,
at concentrations over the critical value, identified it was noticed that F11 prepared with sodium alginate
as critical micellar concentration (CMC). Thus, the had the highest shear thinning effect that indicates a
viscosity of P407 solution increased as the temperature thixotropic behavior. The decrease in viscosity could
is higher than 30˚, the aggregation of poloxamer be attributed to the increased intermolecular distances
molecules into spherical micelles, constituted by a core as a result of thermal expansion with the increase of
of dehydrated hydrophobic propylene oxide (PO) and temperature[55]. It was noticed from the results as
by a shell of hydrated hydrophilic ethylene oxide (EO), comparing F4 to F12, that the drug concentration
results in system gelation[50]. has a non-significant effect on viscosity. This may be
The evaluation for the rheological properties of the ascribed to the amount of drug in the formulation (F4)
in situ gelling liquid suppositories comprising P188, a that could be insignificant.
non-Newtonian flow was a typical property for these
Spreadability measurements were performed only to
formulations at higher temperatures. With continuous
those formulations containing metoclopramide HCl
agitation, all formulations (F4-F6) exhibited pseudo-
with a promising gelation temperature (F4, F7-F11).
plastic flow at 37˚ as it was expected due to their
thermoresponsive property. Otherwise, at higher Formulations (F8, F4, and F7) were studied for their
concentrations of P188, the elastic properties tend to spreadability and it was detected to be satisfactory
increase and interchain entanglements do not have (Table 4). From the data attained, it can be said that
sufficient time to come apart[51]. an increase in HPMC concentration results in a less
From results, it was found that as the concentration spreadability of the prepared in situ gelling liquid
of HPMC K15M increased (F7>F4>F8) the viscosity suppository formulations. A high viscosity and
of in situ gelling liquid suppositories was increased bioadhesive property of the HPMC K15M could be
(Table 3). This was due to the water-absorbing capacity responsible for this decline in the spreadability[56].
of hydrophilic polymers (HPMC K15M), which has The spreadability of the prepared in situ gelling liquid
increased viscosity[52]. suppositories (F9, F10, and F11) was significantly
It was noted that the viscosity of the rectal in situ (p<0.05) decreased as shown in (Table 4). This possibly
gelling liquid suppositories comprising mucoadhesive was as a result of a high viscosity range of these
polymers (F9-F11) increased upon increasing polymers (HPMC K100M, carbopol 934, and sodium
temperature up to 37˚ as shown in (Table 3), and some alginate). Consequently, a high repulsion between
of these liquid suppositories exhibited high viscosity hydrophilic chains and an increased cross-linking
to the extent that affects negatively on the spindle of between hydrophobic chains of the polymer thus a poor
the Brookfield’s apparatus. The flow action of these spreadability may occur[52,57,58].
formulations was increased orderly (F9< F10< F11) TABLE 4: SPREADABILITY AND SYRINGEABILITY
and thus confirmed the pseudoplastic properties of PROPERTIES OF THE SELECTED IN SITU GELLING
these rectal in situ gelling liquid suppositories[13]. It LIQUID SUPPOSITORIES
was noticed that the viscosity of F9 (HPMC K100M) Spreadability
Syringeability (s) Formulations
increased as shown in (Table 3) as the temperature (g cm/s)
increased up to 37˚. Increasing consistency was 7.5±0.77 17.5±0.02 F4
ascribed to enhanced polymeric entanglements, thereby 12.8±0.82 8.8±0.08 F7
increasing the resistance to deformation[53]. Regarding 6.25±0.22 19.5±0.05 F8
F10 (carbopol 934p), it is suggested that increment in 10.82±0.79 11.33±0.13 F9
the number of micelles created will be due to the effect 9.12±0.62 14.5±0.07 F10
of negative coefficient solubility of block copolymer 8.6±0.99 15.7±0.04 F11
micelles. Lately, the micelles turn into closely packed Data were given in mean±SD, n=3
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A syringeability test was conducted to ensure that the release character within approximately 4 h. The results
prepared formulations were having a proper solution of F8, F4, and F7 showed in (fig. 3); elucidated that
flow nature. Moreover, to determine the time taken increasing the polymer concentration (HPMC K15M)
to expel the in situ gelling liquid suppositories to led to retard in the drug release rate. This could be because
the target site by application of a constant force and the drug release from swellable hydrophilic polymer
this termed as syringeability time. Throughout the depends on the thickness of the hydrated layer. Hence,
administration of these liquid suppositories into the increasing polymer concentration led to increasing the
rectum, syringeability time plays a vital role. It is thickness and swelling of the developed gel, giving a
dependent on four parameters: viscosity of in situ longer diffusion path length that considerably reduced
gelling liquid suppositories, concentration of the the penetration of the dissolution medium and slows
polymer, characteristics of needle utilized in the study, down drug release. Moreover, this increment in
and injection flow rate. The latter two parameters polymer concentration results in the formation of a
were kept constant while syringeability time was a strong matrix layer caused by intimate contact between
characteristic of in situ gelling liquid suppositories the particles of HPMC leading to a decrease in mobility
viscosity and imputed to the polymer concentration[59]. of drug particles in swollen matrices, which lead up to
Besides, syringeability time is an alternative a decrease in the drug release[63].
vital parameter for the practical administration of The comparison of the release profile of F4 (HPMC
thermosensitive mucoadhesive polymers that were used K15M) and F9 (HPMC K100M) in (fig. 3) showed the
in this study. As shown in (Table 4) formulations (F7, effect of using different grades of HPMC (0.75 g) on the
F4, and F8) containing ascending order concentration drug release. Thus, the results revealed that increasing
of HPMC K15M which is a long-chained, nonionic HPMC grade led to faster hydration and rapid formation
polymer. Depending on the results, it was detected of a dense and thick gel that slows down further water
that as the concentration of HPMC increased, higher uptake that consequently decreases in drug release.
viscosity and longer syringeability time will be Also, these higher HPMC grades had higher intrinsic
recorded [60]. water holding capacity and the gelled matrices formed
Depending on syringeability studies of prepared in situ from such polymers were less disposed to erosion and
gelling liquid suppository formulations, the differences would reduce the effective molecular diffusion area
among these values in the formulations (F4, F9, F10, and hence decreased drug permeation across the matrix
and F11) was realized to be significant (p<0.05) and as gel[64,65].
shown in (Table 4). This could be referred to as higher Moreover, formulation 11 containing sodium alginate
viscosity of (F9, F10, and F11) as compared to F4 so as shown in (fig. 3) has a slower dissolution rate. This
further syringeability time would be taken to expel
may be due to extensive swelling of the polymer which
these formulations[61,62].
created a high viscosity gel barrier for drug diffusion
Formulations (F1-F12) of metoclopramide HCl that hindered the passage of solvent and leading to a
in situ gelling liquid suppository formulations were decrease in the drug release[66].
characterized via different parameters in this work-
Interestingly, high rectal drug concentration persisted
study (pH, general appearance, drug content, gelation
for up to 4 h after metoclopramide HCl released from
temperature, gel strength, mucoadhesive force, and
in situ gelling liquid suppository formulation, whereas,
viscosity). Thereafter, certain formulations were chosen
to perform the release studies according to the best in- conventional suppositories remained at lower rectal
situ gelling properties they were possessing. These drug concentration. This could be explained by it
formulations were consisting of a constant amount of having a large releasing area, longer retention time,
P407 (15 g) and P188 (2.5 g) with variable amounts and contained more dissolved active ingredient than
of HPMC K15M (0.375 g, 0.75 g, 1.5 g), that were metoclopramide HCl conventional suppository[67]. 
represented in formulations [F8, F4 and F7]. In addition To evolve an ideal kinetic model to interpret the
to the formulations [F9] containing HPMC K100M in vitro drug release data for the selected formulations
(0.75 g) and [F11] containing sodium alginate (0.75 g). in terms of meaningful parameters, various kinetic
The accumulative percentage release of metoclopramide models including zero-order, first-order, Higuchi and
HCl was calculated. Therefore, metoclopramide HCl Korsmeyer-Peppas models were applied to obtain the
with different bases showed almost complete drug best fit for the results.
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Fig. 3: Dissolution profile of metoclopramide HCl from in situ gelling liquid suppository
In situ gelling liquid suppositories containing different concentrations of HPMC K15M [F8 (▬♦▬), F4 (▬■▬), and F7 (▬▲▬)],
HPMC K100M [F9] (▬×▬), and sodium alginate [F11] (▬∗▬), data were given in mean±SD, n=3.

TABLE 5: KINETIC DATA MODELS FOR THE SELECTED IN SITU GELLING LIQUID SUPPOSITORIES
Zero-order First-order Higuchi-order Korsmeyer-Peppas
Formulation
K0(mg h-1) R2 K1(h-1) R2 KH(h-1/2) R2 n Kkp(h-1/3) R2
F4 0.4504 0.9865 -0.0076 0.7901 7.3939 0.9298 0.5190 0.7498 0.9296
F7 0.2741 0.9541 -0.0026 0.9816 5.3731 0.9918 0.5243 0.6531 0.9877
F8 0.3627 0.9943 -0.013 0.7859 5.1115 0.9713 0.2058 1.5378 0.9381
F9 0.3157 0.9853 -0.0033 0.9766 6.0465 0.9776 0.5705 0.5506 0.9496
F11 0.2689 0.9822 -0.0683 0.9876 5.2009 0.9938 0.5832 0.479 0.9944

As shown in (Table 5), it was found that the examination FT-IR spectroscopy was carried out to establish
of the correlation coefficient (R2) for the selected the compatibility of metoclopramide HCl with
formulations indicated that the drug release followed a polymers after the preparation of in situ gelling liquid
diffusion-controlled mechanism from the in situ gelling suppositories. Individual FT-IR scanning of polymers
liquid suppositories, as the values for Higuchi’s square [P188, P407, HPMC K15M] as shown in (fig. 4A, 4B
root of time (ranged from 0.9713 to 0.9938) were and 4C) respectively, the pure drug powder as shown
always higher in comparison to zero-order (ranged in (fig. 4D); in addition to the in situ gelling liquid
from 0.9541 to 0.9943) and first-order (ranged from suppositories of comprising metoclopramide HCl (F4)
0.7859 to 0.9876). The release kinetics of the prepared as shown in (fig. 4E). Moreover, the FTIR of polymers
in situ gelling liquid suppositories illuminated from the with the drug and optimum formula F4 were all
Korsmeyer–Peppas equation that the release exponent reconstructed and showed in (fig. 5).
values (n) for (F4, F7, F9, and F11) were within the
range of 0.5<n<1.0 with the lowest value for F4 and The FT-IR spectrum for pure metoclopramide HCl
the highest value for F11. This observation indicated was characterized by the principal absorption bands at
a non-Fickian (anomalous) release mechanism which 3454.62 cm–1 due to O-H stretching mode of hydrate,
occurs due to a combination of macromolecular chain 3377 cm–1 due to symmetric NH2 stretching vibration,
relaxations and Fickian diffusion. Except for formulation 3311 cm–1 and 3198 cm–1 due to N-H stretching mode
F8 that has a release exponent value (n)<0.5 which of amide, 2980.12 cm–1 and 2877.89 cm–1 due to C-H
was indicative of the Fickian drug release mechanism. stretching, 1631 cm–1 due to C=O stretching of amide,
Hence, it can be deduced from the results that F4 was 1597.11 cm–1 due to NH2 scissoring, 1539.25 cm–1 due
selected as an optimum formula and the drug release to N-H bending, 1265.35 cm–1 due to C-O-C vibration
was mainly following non-Fickian diffusion transport; and 680.89 due to C-Cl vibration[70,71].
this indicated that the drug release mechanism could While FT-IR spectrum of P188 was distinguished
be controlled by swelling of the polymer, followed by by absorption peaks at 2885.6 cm–1 due to aliphatic
drug diffusion through the polymer and slow erosion of stretching of C‑H, 1344.43 cm–1 due to the in‑plane
polymer[68,69]. bending of O‑H, and 1109.11 cm–1 due to stretching

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Fig. 4: The FT-IR spectrograms

FT-IR spectrograms represent 4A: P407, 4B: P188, 4C: HPMC K15M, 4D: metoclopramide HCl (MCP), and 4E: in situ gelling
liquid suppository (F4).

1539 1265.4
3377 685.9
F4 2974 2881 1636
3200
3455 3317.2
MCP
Transmittance

3311
2980.12 2877.89 1631
680.89
3454.62 1536 1265.35
3377 3198
HPMC K15M
1317.43
3462.75 2930.54 1062.81

P188
1344.43
2885.6 1109.11

P407
1348.29
2864.39 1118.75

4000 3500 3000 2500 2000 1500 1000 500

Wave number cm-1

Fig. 5: The FT-IR spectrograms (reconstructed)
661 Indian Journal of Pharmaceutical Sciences June-July 2020
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of C‑O. Moreover, the FT-IR spectrum of P407 was convenient alternative than conventional oral dosage
observed with the characteristic peaks at 2864.39 cm–1 form for emetic patients.
due to aliphatic stretching of C‑H, 1348.29 cm–1 due Acknowledgments:
to in-plane bending of O‑H, and 1118.75 cm–1 due to
stretching of C‑O. Besides, the FT-IR spectrum of The authors would like to thank Mustansiriyah
HPMC K15M was represented by stretching of alkyl University (www. uomustansiriyah. edu. iq) Baghdad-
C-H and phenolic O-H at 2930.54 cm-1 and 3462.75 Iraq for its support in the present work. Also, the authors
cm-1 respectively, the absorption peak at 1317.43 cm-1 would like to give great thanks and appreciation for
that represented stretching of C-O- ether linkage. It assistant professor Dr. A. M. Rasheed in the department
also shows the stretching of the alcohol C-O group at of pharmaceutical chemistry, college of pharmacy,
Mustansiriyah University, Baghdad-Iraq, for his help
1062.81 cm-1[32,72].
and generosity. Deep regards to biorender.com for their
The FT-IR spectrum pattern for in situ gelling liquid facilitation to sketch some figures.
suppository [F4] was compared with the FT-IR
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