Evaluation of Newly Formulated Antiulcer Drug on ...€¦ · mucoadhesive hydrogels are a class of polymeric biomaterials that exhibit the basic characteristic of a hydrogel to swell

J. Drug Res. Egypt, Vol. 35, No.1 (2014) 81

Evaluation of Newly Formulated Antiulcer Drug on Experimental

Ulcer Model

1Nashwah I. Zaki, 2Lobna A. Hassanin and 3Abeer A.M. Khattab

1Dept. of Physiology, (NODCAR), Egypt.

2Dept. of Hormones Evaluation, (NODCAR), Egypt

3Dept. of pharmaceutics, (NODCAR), Egypt

ABSTRACT: The present study was conducted to evaluate the potential gastric protective

and therapeutic effects of ranitidine mucoadhesive hydrogel formulae against ethanol induced

gastric ulceration in rats. Adult female albino rats weighing between 200-220 g ,75 rats for

evaluation of mucoadhesiveness of hydrogel and 70 rats for evaluation of protective and

therapeutic effect of ranitidine hydrogel. The seventy rats were randomly divided into two

experiments, protective and therapeutic effects of newly developed ranitidine mucoadhesive

hydrogel formulae containing polymer mixture of Chitosan and Hydroxypropyl methyl

cellulose (HPMC) at ratio 9:1 (F1) or mixture of Sodium carboxymethyl cellulose (NaCMC)

and HPMC at ratio 9:1 (F2). Each experiment has five groups, seven rats each; group 1 serves

as control and group 2 serves as ulcer control since received a single oral dose of absolute

ethanol (5ml/kg body weight). Group 3 ulcer group received an oral dose of ranitidine

(27mg/kg), while groups 4 and 5 ulcer group received newly formulae of ranitidine F1& F2

respectively. In the present study some gastric parameters as ulcer index, total acidity, gastric

volume and pH besides some biochemical parameters as alanine aminotransferase (ALT),

aspartate aminotransferase (AST) and total antioxidant capacity (TAC), total protein (TP)

level and alkaline phosphatase (ALP) activity were carried out at the end of the experimental

period.The present study showed that F1 revealed more protective and therapeutic potency

than F2 as it was significantly reduced ulcer index, total acidity, gastric volume and pH in

comparison to ulcerated group (p<0.05). Also, the biochemical markers ALT, AST and TAC

were decreased significantly compared to ulcerated group in both experiments. TP level and

ALP activity were altered among different treatments. Moderate improvement in mucus

secretion was recorded for F1 & F2 treatments than the reference drug. The present results

were confirmed by the histopathology findings. Collectively, the current study confirmed the

better therapeutic action of formulae 1 & 2 over the pure drug and that F1 was the most potent

formula. Also, it encouraged the use of F2 as a curative agent of ulceration rather than a

protective one.

Key words: Ranitidine, mucoadhesive hydrogel formulation, liver function markers,

physiological ulcer indexes, mucin secretion

INTRODUCTION: Gastric ulcer is a major health hazard in terms of both

morbidity and mortality (Chaturvedi et al., 2007).

Ulcer therapy has progressed from vagotomy to

anticholinergic drugs, histamine H2 receptor

antagonists, antacids and to proton pump inhibitors

(Wallace & Granger, 1996). Even though the wide

range of available drugs, many of them do not fulfill all

the requirements and have many side effects. Although

histamine H2 receptor antagonist drugs as famotidine

and ranitidine are considered to be the safest one

(Bourdet et al., 2005), these drugs have been reported

to have low bioavailability and short biological half-

life (Hawkins & Hanks, 2000). Ranitidine is a

competitive, reversible inhibitor of the action of

histamine at histamine H2-receptors, including

receptors on gastric cells, with a minimal effect on H1-

receptors (Novak, 2002 and Chavda & Patel, 2010). It

Corresponding author

[email protected]

is one of the drugs of choice for the treatment of active

duodenal ulcers, gastric ulcers, Zollinger-Ellison

syndrome, gastroesophageal reflux disease, and erosive

esophagitis (McCarty-Dawson et al., 1996). The

indicated oral dosage of Ranitidine is 150 mg, twice

daily, or 300 mg once daily. It has been found that the

dose of 300 mg leads to fluctuations in its plasma

levels (Chavda & Patel, 2010). Also, the drug has a

short biological half-life of approximately two to three

hours, an absolute bioavailability of only 50%, and it is

absorbed only in the initial part of the small intestine

(Grant et al., 1989; Lauritsen et al., 1990 and Gramattι

et al., 1994). Colonic metabolism of Ranitidine is also

partly responsible for the poor bioavailability of

Ranitidine from the colon (Basit & Lacey, 2001).

Hence, these drugs have promising future if controlled

release formulations are developed. Several trails have

been used Ranitidine to develop many gastroretentive

drug delivery systems, but it failed in many cases

(Gnanaprakash, 2013). Theoretical and applied studies

stated that gastroretentive mucoadhesive dosage form

can remain in the gastric region for several hours and

hence significantly prolong the gastric residence time

of drugs (Hagerstorm, 2003 and Dua & Trivedi, 2013).

Prolonged gastric retention improves bioavailability,


reduces drug waste. It is also suitable for local drug

delivery to the stomach and proximal small intestines

(Ben et al., 1994 &1996; Hagerstorm, 2003 and Dua,

& Trivedi, 2013). Mucoadhesive dosage forms have

been widely used for site-specific targeting for both

local and systemic drug delivery (Chen et al., 1997;

Nagahara et al., 1998; Harding et al., 1999; Wang et

al., 2000; Cuna et al., 2001 and Bardonnet et al.,

2006). Hydrogels found applications in formulating

controlled and mucoadhesive drug delivery systems

(Bansal et al., 2011). Hydrogels are cross-linked

hydrophilic polymers with a network structure.

Chitosan and Sodium Carboxymethyl Cellulose (Sod.

CMC), have attracted attention. However, these

hydrogels can swell slowly and exhibit low loading

capacities, (Henriksen et al., 1996; Burmania et al.,

2003 and Leonard et al., 2004) which restrict their use

in effective drug delivery. Chitosan, is a linear random

copolymer of D-glucosamine and N-acetyl D-

glucosamine and is obtained by N-deacetylation of

chitin (Domard & Cartier, 1992 and Roberts, 1992).

Chitosan hydrogel can be formed by covalent cross-

linking or ionic cross-linking. By definition,

mucoadhesive hydrogels are a class of polymeric

biomaterials that exhibit the basic characteristic of a

hydrogel to swell by absorbing water and to interact by

means of adhesion with the mucus that covers epithelia

(Nikalje et al., 2012). The goal of mucoadhesive drug

delivery system is to increase the residence time of

therapeutic molecules at the specific sites within the

gastrointestinal (GI) tract for absorption of the drug

into the circulation (Hassan & Gallo, 1990; Roberts,

1992; Takeuchj et al., 1994 and Needleman & Smales,

1995). The approach involves the use of bioadhesive

polymers such as Chitosan - hydroxyl propyl methyl

cellulose (HPMC) that can adhere to the epithelial

surface of the GIT (Sadgir et al., 2014). The adhesion

of the polymers with the mucous membrane may be

mediated by hydration, bonding - or receptor -

mediation (Park & Robinson, 1984). The current study

aimed to assessment the potential gastric protective and

therapeutic effects of ranitidine mucoadhesive hydrogel

formulations on ethanol induced gastric ulcer in rats

compared to ranitidine powder.

MATERIALS AND METHODS: Drugs and chemicals

Ranitidine HCl (R-HCl) was kindly donated by Amoun

pharmaceutical company. Chitosan was purchased

from Sigma, Chitosan (≥ 85% deacetylated, Mol. Wt ~

600,000 Mol. Wt.; ~400 m Pa.s, 1 % in acetic acid at

20 °C, Sigma Aldrich, Germany), Hydroxypropyl

methyl cellulose (HPMC),and sodium carboxymethyl

cellulose (NaCMC) were purchased from Alfa,

Germany. Double distilled water (DDW) was prepared

in the laboratory. All other chemicals used were of

analytical grade.

Preparation of hydrogel formulations

Two formulae were prepared using weighed amount of

polymer mixture of Chitosan and HPMC at ratio 9:1

dissolved in 1% acetic acid to prepare F1; and weighed

amount of polymer mixture of NaCMC and HPMC at

ratio 9:1 dissolved in distilled water to prepare F2.

336 mg of ranitidine HCl was added to each formula.

The formed solutions were casted into Petri dishes and

left to dry at room temperature. Then the dried

hydrogel films were cut into 2 x 2 mm square pieces

and stored in tightly closed container at room

temperature (Paloma et al., 2003).

Experimental animals

Induction of ulcer

All groups under investigation received single oral

dose of absolute ethanol (5ml/kg body weight)

according to the method described by Abdulla et al.

(2010) except the control one.

Evaluation of Mucoadhesiveness of hydrogel

Six week aged female Swiss albino rats weighing 200-

220 g were obtained from the animal house of National

Organization for Drug control and Research

(NODCAR, Giza, Egypt). The animals were

acclimatized in Kafr El Gabal animal house for 2

weeks before the experiment. The animals were fed a

standard diet (El-Nasr Company, Abou-Zaabal, Cairo,

Egypt) and tap water ad libitum, and kept under

controlled conditions of room temperature (21 ± 1 °C),

relative humidity (55±5%) and a 12-h light/12-h dark

cycle. Animals were fasted overnight prior to the

experiment, but were allowed free access to water.

Animals were divided into three groups, each group

contains 25 albino rats, as follows: Group I: (positive

control): this group contained a total of 25 albino rats

and were administrated 5 ml of ranitidine HCl solution

at concentration of 10 mg/ml, Group II: This group

contained a total of 25 rats and administrated a hard

gelatin capsule containing 2 x 2 square particles of

formula I (F1) equivalent to 50 mg ranitidine. Group

III: This group contained a total of 25 rats and

administrated a hard gelatin capsule containing 2 x 2

square particles of formula II (F2) equivalent to 50 mg

ranitidine. At 0.5, 1, 2, 3 and 4 hours following

administration, 5 rats from each group (I, II and III)

were euthanized by cervical dislocation, the stomachs

were excised, cut along the greater curvature, and

gently rinsed by 25 ml of 0.1N HCl and put in

sonicator for dissolving of existed amount of ranitidine

in rinsed solution then filtered through 0.45 µm

Millipore filter. The amount of ranitidine remained was

evaluated by high-performance liquid chromatography

using UV detector at wave length (λmax) 314 nm and C8

column, (250 x 4.6 mm; 5µ). The mobile phase

consisted of 0.05 M potassium dihydrogen phosphate

(pH 3): acetonitrile (25:75 v/v) and was delivered to

the system at a flow rate of 1.2 ml/min. All assays were

performed at ambient conditions. The remaining

percentage of ranitidine as an index of residence in the

stomach, i.e., Mucoadhesiveness, was calculated by the

following equation:

Remaining percentage = (R/T) x100

Where R represents the amount of ranitidine remaining

in the stomach and T represents the amount of

ranitidine administrated. The method was validated for

selectivity, linearity, accuracy and precision (Radi &

Mansoor, 2004).


Evaluation of protective and therapeutic effect of

ranitidine hydrogel To achieve study goals, seventy healthy adult female

Swiss albino rats, weighing between 200-220 g, were

obtained from the animal house at the National

Organization for Drug Control and Research

(NODCAR). They were housed in wire cages with

natural ventilation and illumination and allowed free

water and standard diet for 10 days before beginning of

the experiment. Throughout the experiment, all

procedures, animals and the experimental protocols

were approved by the Institutional Ethics Committee at

NODCAR; and were carried out according to the

criteria outlined in the “Guide for the Care and Use of

Laboratory Animal”. Rats were fasted for 24 h prior to

the experiment but allowed free access to water except

for the last hour before the experiment. All experiments

were performed during the same time of the day to

avoid diurnal variations of putative regulators of gastric

functions.

The animals were randomly divided into two

experiments, the first to study the protective effects

(pre-treated) of newly developed formulae while the

second deals with their therapeutic effects (post-

treated). Each classified into five groups (seven rats

each); Group 1 serves as control (C) while group 2

serves as ulcer control (U), group 3 received ranitidine

(R) as a reference antiulcer drug (27 mg/kg body

weight) equivalent to human recommended dose

(Chavda & Patel, 2010), while groups 4 and 5

received newly formulae of ranitidine with the same

concentration of ranitidine F1 and F2 respectively. In

protective experiment (pre-treated) the animals in each

group were receiving the dose of the treatment as

mentioned above 45 minutes before administration of

5ml of 95% ethanol. After further one hour from

alcohol administration, blood samples were collected

from retro-orbital plexus, then the animals were

scarified by cervical dislocation; the stomach content

was collected, then it was incised along the greater

curvature and examined for gross and histological

evaluation. In therapeutic experiment (post-treated) the

animals were divided as mentioned above. The

treatment was given daily for four successive days on

empty stomach-starting one hour after induction of

ulcer. On the fifth day blood samples were collected,

then the animals were scarified by cervical dislocation

the stomach content was collected and then it was cut

along the greater curvature, washed with saline and

examined for gross and histological evaluation.

Blood sampling

Blood samples were allowed to clot for thirty minutes

at room temperature and then centrifuged at 1000 x g

and 4ºC for ten minutes. The collected serum samples

were stored at -80 ◦C for further estimation of total

protein (TP) content, alanine aminotransferase (ALT),

aspartate aminotransferase (AST), alkaline phosphatase

(ALP) activity and total antioxidant capacity (TAC).

Spectrophotometric procedures were used for their

determination using commercial kit according to

Gornall et al. (1949); Reitman & Frankel (1957); Moss

(1982) and Koracevic et al. (2001) respectively.

Gastric volume and Total acidity

The animals were sacrificed and their stomachs were

cut along the greater curvature, the content of each

stomach was collected into small tubes and centrifuged

at 3000 rpm for 5 minutes. The supernatant was

separated and its volume was measured and expressed

as ml/100 g body weight. The acid content was

determined by titration method with 0.05N NaOH.

Acidity was expressed as mEq/L/100 g of body weight

(Maity et al., 2003).

Acidity= volume of NaOH x normality / 0.1 x100

Macroscopic evaluation of stomach The macroscopic assessment of ethanol-induced gastric

lesions was performed by an independent examiner

who was blinded to the supplementation that the rats

had received. The assessment of lesions was made

according to quantitative scale described by Ismail et

al. (1999). The stomachs were opened along the greater

curvature, rinsed with saline to remove gastric contents

and blood clot then photographed to assess the

formation of ulcers. The numbers of ulcers were

counted. Mean ulcer score for each animal will be

expressed as ulcer index. The scale used was as

follows: 5 = continuous lesions that occupied almost

the entire length of the gastric fold, 4 = lesions which

occupied almost 80% of the entire fold, 3 = presence of

multiple lesions that measure 3mm in length on 80% of

the folds, 2 = presence of at least two lesions

approximately 2mm in length, 1 = presence of a single

lesion with or without generalized erythema, 0.5 =

presence of dot haemorrhage and 0 = no visible

damage.

Curative ratio The curative ratio from the ulcer was calculated

according to Begum et al. (2014) for the treated groups

by using the following equation.

Percentage (%) = [CUI-TUI] /CUI X100

Where, CUI = ulcer index of control groups, TUI =

ulcer index of treated groups.

Histological and Histochemical studies

Gastric tissue specimens from each group were fixed in

10% buffered formalin for twenty four hours. After that

the tissue specimens were washed with tap water then

serial dilutions of alcohol (methyl, ethyl and absolute

ethyl) for dehydration. Specimens were cleared in

xylene and embedded in paraffin at 56 degree in hot air

oven for twenty four hours. Paraffin blocks were

prepared for sectioning at 4 microns thickness by slide

microtome. The obtained tissue sections were collected

on glass slides, deparaffinized, stained by hematoxylin

& eosin stain for routine examination as well as by

alcian blue stain for detection of mucous through the

light electric microscope (Bancroft & Stevens, 1996).

Statistical analysis

The results are presented as the mean ± standard error

( SE) of the six animals used in each group. Statistical

significance was determined by one-way ANOVA at

p< 0.05 followed by Dunnett t (2-sided) for

comparisons between control and other groups while

Duncan posthoc test was used for comparisons among

all treated groups at p<0.05 using the Statistical

Package for the Social Sciences software (SPSS 17).


RESULTS: Evaluation of gastric mucoadhesion

Figure (1) showed the remaining percentage of

ranitidine after 0.5, 1, 2, 3 and 4 hours in the different

groups (I, II and III). It was observed that the remained

amount of ranitidine 4 hours after administration of

mucoadhesive hydrogel formulae F1 and F2 was

55.8±6.5%,45.4±3.5%, respectively compared with

5.6±2.1% after administration of ranitidine powder.

Thus, the mucoadhesive hydrogel formulae seem to be

a potential as oral gastro retentive controlled drug

delivery and targeting its site of action, the stomach,

thus improving its oral bioaviability.

Evaluation of protective and therapeutic effect of

ranitidine hydrogel

Antiulcer parameters

Table (1) showed the effect of pre-treated of R, F1 and

F2 on gastric juice parameters and ulcer parameters. It

was found that ethanol administration caused a

significant increase in pH value, gastric volume and

total acidity; it also caused a remarkably high ulcer

index (2.80± 0.20) as compared with control group.

While, pretreatment with F1 produced a significant

decrease in pH value, gastric volume, and total acidity

as compared to ulcerated group. In the protective study

there was no significant difference between R & F2 in

pH value, gastric volume and total acidity, while F2

showed a significant decrease in total acidity when

compared to ulcerated group. Pre-treatment with R, F1

and F2 offered a significant protection against ethanol

induced gastric ulcer in the experimental rats. Since

Ranitidine reduced the ulcer index to (0.50±0.16)

showing 82.14 % prevention whereas F1 reduced the

ulcer index to (0.10±0.10) showing 96.43% prevention.

While F2 reduces the ulcer index to (1.1±0.24)

showing 60.71% prevention.

Table (2) showed the effect of post-treated of R, F1 and

F2 on gastric juice parameters and ulcer parameters. It

was observed that ethanol administration caused non-

significant changes in pH value and gastric volume

while total acidity was increased significantly as

compared with control group, also caused ulcer index

(2.20±0.20). Post-treatment with R, F1 & F2 resulted

in a significant reduction in pH value. Gastric volume

showed a non-significant increase in all treated groups.

Post-treatment with F1 showed a significant reduction

in total acidity as compared to ulcerated group. While

R & F2 revealed a non-significant change in total

acidity. Post-treatment with R, F1 & F2 produced a

significant healing reached to 63.64%, 81.82% and

77.27% respectively.

Biochemical parameters

It was found that oral administration of ethanol caused

a significant decrease in serum total protein (TP) in

both pre- and post-treated experiments as compared

with control group (tables 3 and 4). Pre-treatment with

F1 and F2 showed a non-significant change in total

protein as compared to ulcerated group. A significant

increase in serum total protein levels were observed in

F1 & F2 post-treated rats while non-significantly

increased in R post-treated as compared to ulcerated

group.

Ethanol administration showed a significant increase in

the activities of the hepatic enzymes ALT& AST as

compared to control group (tables 3 and 4). While the

administration of F1& F2 in both pre- and post-

treatment experiments resulted in a significant decrease

in serum activity of these hepatic enzymes when

compared to their activities in ethanol treated rats.

Ranitidine administration caused a significant decrease

in hepatic enzymes activity in the pre- treated rats and a

non-significant increase in post-treated rats as

compared to ulcerated group.

It was observed that ethanol caused a significant

decrease in ALP levels and a significant increase in

TAC level when compared with control group. Oral

administration of R, F1 & F2 in pre- and post-treated

rats significantly increased ALP level as compared

with ulcerated group. Pre-treatment with F1 revealed a

significant decrease in TAC as compared with

ulcerated group while R and F2 showed a non-

significant decrease. Whereas post-treatment with R,

F1 & F2 revealed a significant reduction in TAC when

compared with ethanol treated group tables (3 & 4).

Histopathological studies

The severity of histopathological changes in stomach

of different treatments as pre- and post-treatments was

summarized in tables (5) & (6) respectively. Table (5)

showed that pretreatment with F1 before ethanol had

alleviated the effect of ethanol. Thereby F1 was more

effective than R & F2 groups. Table (6) revealed that

post-treatment with R, F1 & F2 decrease the sever

ulcer induced by ethanol. Formula 2 was more

effective than R & F1 treatments.

Histochemistry studies

Histochemical studies Plate (1) showed that; in the

control group; the mucous secretion was localized in

the superficial surface and in the lining epithelium of

the glandular structure. Rat's stomach under the

protective (pre-treated) experiment revealed marked

alteration compared to control group where, very few

mucous was noticed in the mucosal layer among

ulcerated rats. While rats administered ranitidine, the

intact mucosa and glandular structure showed mucous

secretion. F1 treated rats revealed minor alterations

where, the blue color of the mucous was noticed in the

desquamated mucosal epithelium as well as in the

underlying intact glandular structure. In the other hand,

the mucous was localized in the deep intact glandular

structure of the mucosa among rat treated with F2. In

rats experimentally induced ulcer and sacrificed after

four days (post-treated); the mucous was absent from

the mucosa. There was very few mucous in the

ulcerated surface of Ranitidine (post-treated) group.

Rats under F1 treatment showed that mucous was

localized in the deep layer of the mucosa in the glands.

While in F2 rats group, little mucous secretion was

detected in the deep area of the mucosal epithelium.

DISCUSSION: The main target of this research was to evaluate the

healing efficacy of the two newly developed

gastroretentive drug delivery system with ranitidine

F1& F2 to meet the therapeutic needs relating to


experimental pathological conditions in rats as gastric

ulcer. Also, assessed their role in augmenting the

mucosal defense against ethanol induce gastric ulcer.

Disturbances in gastric indices parameters include

ulceration; necrosis in mucosa; hemorrhage; odema in

mucosa and submucosa beside inflammatory reaction

in submucosa. As well as depletion of gastric mucus

were recorded in the present study to alcohol

administration. Ethanol–induced gastrointestinal lesion

implicates a variety of mechanisms. It has been

reported to cause disturbances in gastric secretion,

damage to the mucosa, alterations in the permeability,

gastric mucus depletion and free radical production

(Al-Howiriny et al., 2003; Vinothapooshan & Sundar,

2010; Choudhary et al., 2014 and Olaibi et al., 2014).

These may be attributed to the release of superoxide

anion and hydroperoxy free radicals during metabolism

of ethanol. In accordance, oxygen derived free radicals

has been found to be involved in the mechanism of

acute and chronic ulceration in the gastric mucosa

(Jude & Paul, 2009). Alcohol rapidly penetrates the

gastric mucosa apparently causing cell and plasma

membrane damage leading to increase intracellular

membrane permeability to sodium and water which

evident by the current histopathology finding since

odema present in all alcohol treatments. The massive

intracellular accumulation of calcium represents a

major step in the pathogenesis of gastric mucosal

injury. This leads to cell death and exfoliation in the

surface epithelium (Raju et al. 2009). In the current

study, it has been shown that pre-treatment or post-

treatment with F1 & F2 ameliorated the deleterious

effects of ethanol on ulcer index parameters with

advantage of F1. Bioadhesive dosage form (Nagahara

et al., 1998 and Wang et al., 2001) extend the

residence time of the drug in the stomach, the extended

release of the drug can maintain a higher drug

concentration in the gastric region thereby, improve the

absorption and systemic bioavailability of the drugs

that were normally poorly absorbed (Nagai & Machida,

1985) and improve the therapeutic efficacy. This may

be due to local cytoprotective enhancement by the two

formulae via their bioadhesion properties (adhering to

epithelium) and mucoadhesion properties (adhering to

mucus), since these formulations allow more

opportunity to contact the epithelium or mucus and

topically coating the injured tissue for facilitating

healing. Also, they offer significant potential for

increasing gastrointestinal tract residence time leading

to improved ranitidine bioavailability (Hemant et al.,

2010). Gastric mucus (mucin) is an important

protective factor for the gastric mucosa and consists of

a viscous, elastic, adherent and transparent gel formed

by 95% water and 5% glycoproteins that cover the

entire gastrointestinal mucosa. Moreover, mucus is

capable of acting as an antioxidant, and thus can reduce

mucosal damage mediated by oxygen free radicals

(Repetto & Llesuy, 2002). The protective properties of

the mucus barrier depend not only on the gel structure

but also on the amount or thickness of the layer

covering the mucosal surface (Penissi & Piezzi, 1999).

In the present study, decreased mucin secretion

after ethanol treatment indicating reduced ability of the

mucosal membrane to protect the mucosa from

physical damage and back diffusion of hydrogen ions.

Mucosal damage can be easily produced by the

generation of exogenous and endogenous free radicals

(Naito et al., 1995). An increase in mucus production

usually assists the healing process by protecting the

ulcer crater against irritant stomach secretions (HCl

and pepsin) thereby enhancing the rate of the

local healing process. F1 & F2 protected the gastric

mucosa from damage by increasing the mucin content

significantly as evident by the current histochemical

micrographs. The advantage of F1 may be attributed to

gastric mucus layer enhancement probably by

increasing the generation of mucosal prostaglandin E2

(Dashputre & Naikwade, 2011). Prostaglandin E2 was

known to be a strong stimulant for gastric mucus

secretion due to the presence of chitosan (Ishihara et

al., 2001), and its likely reflect an increase in the newly

secreted adherent mucus which consider to be more

important as a protective physical barrier of gastric

epithelium as supported by the current histochemical

finding. In the present study ethanol administration

revealed a significant decrease in serum total protein

levels in both experiments concurrent with significant

increase in ALT & AST enzymes activities indicating

hepatic injury (Myagmar et al., 2004). These results are

in accordance with Ahmed et al. (2002); Hornyak et al.

(2003); Nwoye, (2013) and Choudhary et al., (2014).

Improved total protein levels estimated in the current

study among F1 and F2 treatments in pre and post-

treated rats respectively than R treatment to the fact

that mucoadhesive dosage formulae increase the

absorption and systemic bioavailability of the drugs

that normally poorly absorbed as ranitidine (Hemant et

al., 2010). Also, it may be attributed to the

immunomodulatory and inflammatory properties of

ranitidine which improved by the current

mucoadhesive formulae F1 and F2 and evidenced by

the current histologic findings since the presence of

mild to moderate inflammatory cells infiltration could

motivate the immune responses. In addition, F1 & F2

had a greater protective effect than ranitidine on

hepatocytes against ethanol-induced damage and

subsequent leakage of enzymes into the circulation.

These results are in accordance with Choudhary et al.,

2014. On the other hand, a significant decrease in ALP

levels observed in ethanol treated rats was in agreement

with the study observed by Ahmed et al. (2012). Oral

administration of F1 & F2 was significantly increased

ALP level among pre- and post-treatments. Therefore,

it is possible that the differences in the effectiveness

between the two formulae may be due to the strength

and duration of adhesiveness of the developed

formulae to the mucosa or the ulcerated area with the

advantage of the local effects over the systemic one.

Conclusion: The current study throw some lights on

the role of mucoadhesive hydrogel formulations

against ethanol induced gastric ulcer in rats and

confirmed the better therapeutic action of these

formulae over the pure drug which might be a

promising drug delivery system for the ulcer treatment.

The mucoadhesive hydrogel formulations of chitosan

and Sod. CMC not only provide an excellent


preventive effect in gastric ulcer models, but also

possesses a significant hepatoprotective effect. Also, it

encouraged the use of F1 formulae as protective and

therapeutic agent of ulcer since F1 was the most potent

one and formula with Sod. CMC as a therapeutic agent.

Further physiological studies needed to explore the role

of chitosan in gastric inflammation induced by

different factors.

0

10

20

30

40

50

60

70

80

90

100

%

rem

ain

ing

of

ran

itid

ine

0.5 1 2 3 4

Time(hr)

GroupI

GroupII

GroupIII

Figure (1): Remaining percentage of ranitidine in the stomachs of albino rats at different time intervals after oral

administration of F1 (group I), F2 (group II) and ranitidine solution (group III).

Table (1): Effect of different formulae on some gastric mucosal parameters as protective agents (pre-treated)

against standard ranitidine treatment.

- Results were expressed as mean±SE for each 6 rats.

-* Significance difference versus control at P < 0.05.

- Groups have the same letter mean non- significant

while groups have different letters means significant at P < 0.05.

Table (2): Effect of different formulae on some gastric mucosal parameters as therapeutic agents (post-

treatment) against standard ranitidine treatment.




while groups have different letters means significant at P < 0.05

Treatment

Parameters

PH GV

ml

Total acidity

mEq/Lit Ulcer index

Curative ratio

C 5.56a±0.218 1.238c±0.018 25.30b±1.393 0.00a±0.00 -

U 7.48*b±0.218 3.28*b±0.102 58.00*d±2.55 2.80*c±0.20 -

R 7.60*b±0.114 2.98*ab±0.391 54.00*d±2.898 0.50*a±0.16 82.14%

F1 5.53a±0.189 2.44*a±0.178 13.00*a±1.140 0.10a±0.10 96.43%

F2 7.34*b±0.196 3.60*b±0.187 36.00*c±1.871 1.1*b±0.24 60.71%

Treatment

Parameters

PH GV

ml

Total acidity

mEq/Lit Ulcer index

Curative ratio

C 5.54c±0.220 1.244a±0.012 25.10a±1.756 0.00a±0.00 -

U 5.65c±0.022 1.320a±0.046 44.00*c ±1.696 2.20*c±0.20 -

R 4.82*b±0.107 1.320a±0.026 40.20*bc ±2.818 0.80*b±0.12 63.64%

F1 4.06*a ±0.284 1.284a±0.035 37.20*b ±2.518 0.40b±0.19 81.82%

F2 3.76*a±0.083 1.268a±0.036 46.20*c±1.855 0.50*b±0.00 77.27%


Table (3): Effect of different formulae on some serum biochemical parameters as protective agents (pre-

treated) against standard ranitidine treatment .





Table (4): Effect of different formulae on some serum biochemical parameters as therapeutic agents (post-

treatment) against standard ranitidine treatment.

-Results were expressed as mean±SE for each 6 rats.

*Significance difference versus control at P < 0.05.

-Groups have the same letter mean non- significant


Table (5): Severity of histopathological reaction in stomach of different treatments as protective agents(pre-

treated) . Histopathologly Alterations


*+++ = Sever effect; ++= Moderate effect; + Mild effect& ـــ Nil

Table (6): Severity of histopathological reaction in stomach of different treatments as therapeutic agents(pre-

treated) . Histopathologly Alterations


*+++ = Sever effect; ++= Moderate effect; + Mild effect& ـــ Nil

Treatment

Parameters

TP

mg/dl

ALT

U/L

AST

U/L

ALK

U/L (37°C)

TAC

mM/L

C 7.46c±0.21 20.743a±0.66 30.029b±0.43 44.382b±1.621 2.059a±0.002

U 6.86ab±0.22 26.072*c±0.39 38.399*c±0.53 22.724*a±1.856 2.129* c ±0.002

R 7.03bc±0.15 21.058ab±0.55 28.626b±0.43 49.207b±2.672 2.105b*c±0.007

F1 6.42*a±0.11 19.922a±0.54 27.067*a±0.33 54.438*c±2.735 2.079ab±0.023

F2 7.12bc±0.11 22.696b±0.73 29.427b±0.56 27.434*a±1.164 2.101bc±0.008

Treatment

Parameters

TP

mg/dl

ALT

U/L

AST

U/L

ALK

U/L (37°C)

TAC

mM/L

C 7.46c±0.21 20.743a±0.66 40.029a±0.43 44.378d±0.596 2.059b±0.001

U 6.28*a±0.19 30.704*c±0.29 55.756*c±0.49 20.616*a ±1.047 2.129*c±0.002

R 6.70*ab±0.15 23.530*b±0.63 57.416*c±0.48 28.444*b ±0.754 2.033*a±0.003

F1 7.15bc±0.12 23.673*b±0.92 45.062*b±0.45 46.558d±2.417 2.053b±0.007

F2 6.85*b±0.12 23.035b±0.61 41.461a±0.60 34.494*c ±2.954 2.075*d±0.002

Treatment Ulceration

( mucosa)

Necrosis

( mucosa)

Inflammation Reaction

(submucosa)

Haemorrhage

(mucosa& submucosa)

Degree

Of Severity

C ــــ ــــ ــــ ــــ ــــ

U ــــ ++ + + ++

R ــــ ــــ +++ ــــ ــــ

F1 ــــ ــــ ــــ ــــ ــــ

F2 ++ + + ++ ++

Treatment Ulceration

( mucosa)

Necrosis

( mucosa)

Inflammation Reaction

(submucosa)

Haemorrhage

(mucosa& submucosa)

Degree

Of Severity

C ــــ ــــ ــــ ــــ ــــ

U +++ +++ + + +++

R ــــ ــــ + ++ ــــ

F1 ــــ ــــ ++ ــــ ــــ

F2 ــــ ــــ + ــــ ــــ


Photomicrograph (1) Stomach of control rats showing normal histopathological structure the mucosa(mu), submucosa

(sm), muscularis (ml) and serosa(s).H&E(A =X16); (B =X40).

Photomicrograph (2) Stomach of ulcerated rats (Pre-treated) showing necrosis (nmu) and hemorrhage (h) in mucosa

with oedema (O) and few inflammatory cells infiltration(m) in submucosa. H&E (A =X16); (B =X40)

Photomicrograph (3) Stomach of ranitidine treated rats (Pre-treated) showing inflammatory cells infiltration (m) and

congestion in blood vessel (v) of the sub mucosa. H&E (A =X16); (B =X40)

Photomicrograph (4) Stomach of formula (1) treated rats (Pre-treated) showing intact mucosa (mu) with odema(O) in

the sub mucosa. H&E (A =X16); (B =X40).

Photomicrograph (5) Stomach of formula (2) treated rats (Pre-treated) showing ulceration with haemorrhage(h) in

superficial mucosal layer (umu), lamina propria and submucosa. H&E (A =X16); (B =X40).


Photomicrograph (6) Stomach of ulcerated rats (Post-treated) showing ulceration and haemorrhage (umu) in mucosa

with dilation in blood vessels (v), oedema (O) and few hemorrhage (h) in submucosa. H&E(A =X16); (B =X40).

Photomicrograph (7) Stomach of ranitidine treated rats (Post-treated) showing necrosis and desquamation of the

superficial mucosa (nmu) with inflammatory cells infiltration(m), oedema (O) and mild congestion in blood vessel (v)

in the sub mucosa. H&E(A =X16); (B =X40).

Photomicrograph (8) Stomach of formula (1) treated rats (Post-treated) showing intact mucosa (mu) with odema(O) ,

hemorrhage (h), congested blood vessel (v) and inflammatory cells infiltration(m) in sub mucosa. H&E (A =X16); (B

=X40).

Photomicrograph (9) Stomach of formula (2) treated rats (Post-treated) showing intact mucosa (mu) with odema(O)

in the sub mucosa and few inflammatory cells infiltration (m) in sub mucosa. H&E (A =X16); (B =X40).


Histochemical findings:- Detection of mucous

Plate. 1: Stomach tissue of albino rat treated with different formulae using alcian blue; (Con) Stomach tissue of control

albino rat, showing mucous localized in diffuse manner all over the mucosal epithelial cells (arrow) X: 40.; (U pre-)

Ulcerated rat, showing absence of the mucus from the mucosal epithelium (arrow) X:40 . (U post-) Ulcerated rat

showing very few amount of mucus in the mucosal epithelium (arrow) X:40. (R pre-) Ranitidine treated rats, showing

very few amount of mucus in the mucosal epithelium (arrow) X:40; (R post-) Showing localization of mucus in the

epithelium of the deep mucosa (arrow), X: 40.; (F1 pre-) formula 1 treated animals showing blue color of mucus in the

desquamated mucosal epithelium as well as in the underlying intact one (arrow), X: 40.; (F1 post-) Showing localization

of mucus in the intact mucosal epithelial cells (arrow) X:40.(F2 pre-) formula 2 treated animals showing few amount of

mucus in the intact deep mucosal epithelial cells (arrow);

(F2 post-) Showing localization of mucus in the deep intact glandular mucosal structure (arrow), X: 40.

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تقييم صياغات دوائية جديدة ألحد مضادات القرح على نموذج تجريبي للقرحة

عبير مصطفى خطاب3لبنى عبد المنعم محمد حسنين, 2نشوة اسماعيل زكى, 1 الهيئة القومية للرقابة والبحوث الدوائية -شعبة الفسيولوجى -1

الهيئة القومية للرقابة والبحوث الدوائية -شعبة تقييم الهرمونات -2

الهيئة القومية للرقابة والبحوث الدوائية -شعبة الصيدالنيات -3

ى قرحة المعدة من االمراض الشائعة فى العصر الحديث ، وهى تحدث نتيجة عدم التوازن بين العصارة المعدية الهاضمة والعوامل المختلفة الت

أثير الهدام لهذه العصارة. وتعالج القرحة اما بمعادل للحموضة، او مثبط للعصارة المعدية ، او مواد تحمى االغشية تحمى جدار المعدة من الت

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اعتبرت بمثابة ( 1جرذان , كل الجرعات تأخذ عن طريق الفم. المجموعة ) 6.كل تجربة بها خمس مجموعات وكل مجموعة بها 1:9بنسبة

( 3) مجم/كجم من وزن الجسم( , المجموعة 5( بمثابة مجموعة القرحة الضابطة حيث تلقت ايثانول ) 2الضابطة والمجموعة رقم )المجموعة

. وقد تم بالترتيب F2,F1 ( الصيغ الجديدة للرانيتيدين5( و )4مجم/كجم من وزن الجسم(, بينما تلقت المجموعتان )27تلقت عقار الرانيتيدين )

وقد تبين من هذه TAC و ALT و AST و حجم العصارة المعديةلهيدروجيني و الحموضة الكلية و مؤشر القرحة و االس اتقدير كل من

الهيدروجيني و الحموضة حيث انه قلل مؤشر القرحة و االس كعقار وقائي و عالجي F2 من الصياغة اكثر فاعلية F1 الدراسة ان الصياغة

مقارنة AST, ALT, TACعدية مقارنة بمجموعة االيثانول. وقد لوحظ ايضا نقصان معنوي في مستوى كال من حجم العصارة الم الكلية و

بمجموعة االيثانول في كال من التجربتين. و حدثت بعض االضطرابات في مستوي البروتين الكلي ونشاط انزيم الفوسفاتيز القاعدي. لقد تحسن

الرانيتيدين )الدواء المرجعي( حيث أكدت هذه النتائج بواسطة الدراسات اكثر من مستوى الميوسين في التحضيرات الجديدة

وهذا يدل علي انها F1. وقد وجد ان كمية الرانتيدين المتبقية في المعدة بعد اربعة ساعات هي االكثر في حالة والهستوكيميائية الهستوباثولوجية

لهم F2,F1كمية كافية من العقار وتزيد االتاحة الحيوية له. اخيرا هذه الدراسة توضح ان من افضل الصياغات التي تلتصق بجدارالمعدة وتبقي

كعالجي اكثر منه كوقائي. F2اكثر فاعلية وايضا يجب تشجيع استخدام F1تأثير عالجي افضل من الرانتيدين منفردا ولكن

Evaluation of Newly Formulated Antiulcer Drug on ...€¦ · mucoadhesive hydrogels are a class of polymeric biomaterials that exhibit the basic characteristic of a hydrogel to swell

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