http://informahealthcare.com/drdISSN: 1071-7544 (print), 1521-0464 (electronic)

Drug Deliv, Early Online: 1–6! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10717544.2014.891273

RESEARCH ARTICLE

Formulation and characterization of floating microballoons ofNizatidine for effective treatment of gastric ulcers in murine model

Akash Jain1, Vikas Pandey1, Aditya Ganeshpurkar2, Nazneen Dubey2, and Divya Bansal1

1Pharmaceutics Research Laboratory and 2Drug Discovery Laboratory, Shri Ram Institute of Technology-Pharmacy, Jabalpur,

Madhya Pradesh, India

Abstract

Background: The purpose of the present study was to formulate and characterize Nizatidine-encapsulated microballoons for enhancing bioavailability and increasing the residence time ofdrug in the gastrointestinal tract.Methods: Microballoons were prepared using emulsion solvent diffusion method using EudragitS-100 and HPMC as the polymer. The formulation process was optimized for polymer ratio,drug: polymer ratio, emulsifier concentration, stirring speed, stirring time. Optimizedformulation was subjected to scanning electron microscopy, drug entrapment, buoyancystudies, in-vitro drug release and in-vivo floating efficiency (X-ray) study. In-vivo antiulcer activitywas assessed by ethanol-induced ulcer in murine model.Results: The microballoons were smooth and spherical in shape and were porous in nature dueto hollow core. A sustained release of drug was observed for 12 h. Examination of thesequential X-ray images taken during the study clearly indicated that the optimized formulationremained buoyant and uniformly distributed in the gastric contents for a period of 12 h.In ethanol-induced ulcer model, drug-loaded Microballoon-treated group showed significant(p50.01) ulcer protection index as compared to free drug-treated group.Conclusion: Nizatidine-loaded floating microballoons may serve as a useful drug delivery systemfor prolonging the gastric residence time and effective treatment of gastric ulcers.

Keywords

Buoyancy, ethanol-induced ulcer,microballoons, nizatidine, X-rays

History

Received 18 January 2014Revised 2 February 2014Accepted 2 February 2014

Introduction

Oral administration suffer from the drawback of having

incomplete drug release from device and short residence time

of the pharmaceutical dosage form resulting in poor bioavail-

ability of drug in the gastrointestinal tract (GI) (Tayade &

Kale, 2007). Hence sustained release dosage forms have been

designed to both prolong gastrointestinal transit of the dosage

form as well as controlled drug release. Several gastrointes-

tinal targeting dosage forms (Moes, 1993; Deshpande et al.,

1997; Hwang et al., 1998), including intragastric flotation

systems (Yuasa et al., 1996; Rouge et al., 1998; Lee et al.,

1999), high-density systems (Hwang et al., 1998), mucoad-

hesive systems, adhesion to the gastric mucosal surface in

order to extend gastric residence time (GRT) (Akiyama et al.,

1995), magnetic systems (Groning et al., 1998), unfoldable,

extendible, or swellable systems (Fix et al., 1993) and

superporous hydrogel systems (Park, 1988), have been

developed.

One such approach is floating drug delivery systems

(FDDS) in which the system floats over the gastric contents

and drug is released slowly at the desired rate. These systems

can be used for drugs possessing solubility in acidic

environment and high rate of absorption in the upper part

of the small intestine (Deshpande et al., 1997; Arora et al.,

2005). Both single and multiple unit systems have been

developed. High variability of gastrointestinal transit time,

due to its all-or-nothing gastric emptying process is the

disadvantage associated with single unit system. Thus, a

multiple-unit floating system which distributes widely

throughout the GI has been developed. Sato et al. (2003)

developed a multiple-unit floating system involving hollow

microspheres (microballoons) with excellent buoyant proper-

ties using o/w emulsion solvent diffusion method.

Microballoons are in a strict sense, spherical empty particles

without core having internal hollow structure with air inside.

Microballoons incorporate a drug dispersed or dissolved

throughout particle matrix have the potential for controlled

release of drugs (Ojha et al., 2006).

Nizatidine is a histamine H2-receptor antagonist that

inhibits stomach acid production, and commonly used in the

treatment of peptic ulcer disease (PUD) and gastroesophageal

reflux disease (GERD). Nizatidine is absorbed from the upper

GI and is preferentially localized in parietal cells of gastric

mucosa. The short half-life (1–2 h) and rapid clearance of

nizatidine suggest it a rationale drug for gastroretentive drug

Address for correspondence: Dr. Divya Bansal, Associate Professor,Pharmaceutics Research Laboratory, Shri Ram Institute of Technology-Pharmacy, Jabalpur, Madhya Pradesh 482002, India. Tel: 0761-4001921.Fax: 0761-4001931. Email:drdivyabansal1126@gmail.com

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delivery. The high solubility, chemical and enzymatic stability

and absorption profile of nizatidine in acidic pH values

(of stomach), points to the potential of gastroretentive dosage

form. The present works aims to design gastroretentive drug

delivery system for nizatidine using microballoons as the

carrier system that could give site specific and controlled drug

release.

Materials and method

Nizatidine were obtained as gift samples from M/s

Dr Reddy’s Labs. Hyderabad. Eudragit S-100 was purchased

from Rohm Pharma. Gmbh, Germany and HPMC,

Dichloromethane, methanol, polyvinyl alcohol (PVA) and

Tween 80 were purchased from Central Drug House, Mumbai

(India). All other chemicals used were of analytical grade.

Preparation of microballoons

Microballoons were prepared using the emulsion solvent

diffusion method (Kawashima et al., 1992). Nizatidine (0.1 g),

polymers (1.0 g) and monostearin (0.5 g) were dissolved in a

mixture of dichloromethane (8 ml) and ethanol (8 ml) at room

temperature. Each solution was introduced into an aqueous

solution of PVA (0.75 w/v%, 200 ml) at 40 �C. Resultant

emulsion was stirred at 300 rpm with a propeller type agitator

for 1 h. The resulting polymeric spheres were dried overnight

at 40 �C.

The formulation process was optimized for polymer ratio,

drug: polymer ratio, emulsifier concentration, stirring speed,

stirring time (Table 1). On the basis of formulation and

process variables, the optimized conditions for preparation of

microballoons were recorded in Table 2.

Characterization of microballoons

Electron microscopy

Scanning electron microscopy (SEM, Jeon Scanning Electron

Microscpe J.S.-840) was performed to characterize the

surface of formed microspheres. The samples for SEM were

prepared by lightly sprinkling the microballoons on a double-

adhesive tape stuck to an aluminum stub. The stubs were then

coated with gold to a thickness of about 300 A under argon

atmosphere using a gold sputter module in a high-vacuum

evaporator. The samples were then randomly scanned using a

Scanning Electron Microscope and photomicrographs were

captured.

Entrapment efficiency

Microballoons containing drug equivalent to 100 mg

Nizatidine were digested in a 10 mL mixture of dichloro-

methane and methanol (1:1 v/v). The mixture was centrifuged

at 3000 rpm for 3 min and 1 ml of supernatant was withdrawn

and after suitable dilution with distilled water and assayed

spectrophotometrically. The percentage drug entrapment is

calculated from the equation given below.

% Entrapment Efficiency

¼

Amount of drug in

microballoons formulation

� �

Theoritical amount of

drug in the preparation

� � � 100:

In-vitro buoyancy

Microballoons (100 mg) were dispersed in USP dissolution

apparatus containing simulated gastric fluid (SGF 900 ml, pH

1.2, 37 �C) containing Tween 20 (0.02% w/v). It was stirred

with a paddle at 100 rpm for 12 h. After predetermined time

interval, the layer of floating particles was separated from

settled particle. Both fractions of particles were dried in

vacuum desiccators. Both the fractions of microballoons were

weighed and buoyancy was determined by using the formula:

Buoyancy ð%Þ ¼ Wf

Wf þWs

� 100:

where Wf and WS are the weights of the floating and sinking

microballoons, respectively.

In-vitro drug release study

The drug release study was carried out in USP paddle type

dissolution apparatus (Veego, DA-6DR USP). Microballoons

containing drug equivalent to 100 mg were gently spread over

the surface of 900 ml of dissolution media (SGF, pH 1.2). The

speed of rotation was maintained at 100 rpm and the

temperature of dissolution medium was thermostatically

controlled at 37 ± 2 �C. The samples were withdrawn at

suitable time interval from the dissolution apparatus. The

initial volume of fluid was maintained by adding fresh

Table 1. Process variables of nizatidine-loaded microballoons.

Formulationvariable

Particlesize (mm)

% Entrapmentefficiency

% Buoyancy(after 6 h)

Polymer ratio1:1 268.6 ± 4.6 51.4 ± 3.2 65.6 ± 3.41:2 272.4 ± 6.8 56.7 ± 2.8 79.4 ± 3.81:3 292.8 ± 4.3 65.4 ± 4.6 81.8 ± 2.81:4 308.5 ± 2.4 59.3 ± 3.8 73.4 ± 4.2

Drug:Polymer ratio1:1 266.6 ± 4.3 56.8 ± 3.6 65.2 ± 3.21:2 271.4 ± 6.2 60.6 ± 2.2 78.5 ± 4.51:3 290.5 ± 4.1 68.2 ± 4.2 85.6 ± 2.41:4 292.8 ± 1.4 68.2 ± 4.1 79.5 ± 2.8

Emulsifier concentration (%w/v)0.50 292.7 ± 3.3 67.6 ± 3.5 86.6 ± 2.80.75 284.2 ± 4.6 61.2 ± 4.8 84.3 ± 4.11.00 262.4 ± 3.6 59.6 ± 3.4 81.6 ± 2.21.25 249.6 ± 4.2 55.6 ± 2.8 72.8 ± 4.6

Stirring speed (rpm)300 304.4 ± 2.4 69.4 ± 1.2 80.4 ± 2.6500 290.2 ± 5.2 64.8 ± 4.2 83.64 ± 3.2700 274.6 ± 3.6 59.8 ± 5.2 74.8 ± 4.6

Table 2. Formula for the preparation of microballoonsafter optimization.

Optimized parameter Value

Polymer ratio 1:3Drug: polymer ratio 1:4Emulsifier concentration (%w/v) 0.5Stirring speed (rpm) 900Stirring time (hour) 3

2 A. Jain et al. Drug Deliv, Early Online: 1–6

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dissolution fluid after each withdrawal. The samples with-

drawn were assayed spectrophotometrically using UV–visible

spectrophotometer (Shimadzu 1701, Japan).

In-vivo floating efficiency (X-ray) study

The in-vivo study was carried out by administering floating

beads to rats and monitoring them by a radiological method

(Rajinikanth & Mishra, 2007) with slight modifications. Six

healthy albino rats of either sex, weighing 400–500 g were

used for the present study. The animals were housed in

individual cages, and the experiments were conducted in a

sanitized room at a temperature maintained at around 27 �C.

Food was withdrawn 12 h prior to the study with water ad

libitum. To make the beads radiopaque, 500 mg of barium

sulfate was incorporated into polymeric solution (the same

optimized formulation composition was used to prepare

radiopaque beads) and radiopaque beads were prepared

using a similar procedure to that mentioned in the preparation

of beads. Beads were administered through oral gastric tube

with 2 ml water in fasted state. The animals were not allowed

to eat or drink throughout the study (up to 6 h). In total, 1 ml

of water was administered to animals every hour throughout

the study. The position of bead in the rat’s stomach was

monitored by X-ray photographs (Siregraph-B, Siemens,

Germany) of the gastric region at varying time intervals

(at 1, 4 and 6 h). The protocol of the study was approved by

Animals Ethical Committee, Shri Ram Institute of

Technology-Pharmacy, Jabalpur, India (Protocol No: SRITP/

IEAC/12/05).

Antiulcer activity

This investigation was conducted on Albino rats, with an

average body weight of 400–450 g and ages up to 3 months.

Animals were kept in standard cages at constant room

temperature 25 ± 1 �C, with circadian rhythm (day/night), and

were fed standard laboratory rat feed. Before the experiment,

all animals were exposed to a 24-h fasting period prior to

treatment with alcohol, but had free access to water. Alcohol

stress was induced by intragastric administration of 1 ml of

100% alcohol (Arafa & Sayed-Ahmed, 2003). The animals

were divided into three groups, each consisting of five rats.

First group received normal saline. Nizatidine solution

(10 mg/ml) was administered orally to animals of second

group. Third group received nizatidine-loaded microballoons

(equivalent to 10 mg). Upon treatment, animals were

sacrificed, and the abdomen was opened by midline incision,

the stomach was removed, opened along the greater curvature,

rinsed gently with water, and pinned open for macroscopic

examination. Areas with gastric lesions were measured and

the ulcer index (UI) was estimated from the formula:

UI ¼ ½ulcerated area ðmm2Þ=total stomach area ðmm2Þ�:

Results

Formulation and optimization of microspheres

Floating microballoons were prepared by emulsion solvent

diffusion method using Eudragit S-100 and HPMC.

Formulations were optimized by using varying concentration

of Eudragit S-100 and fixed concentration of HPMC to

evaluate the effect of polymer concentration on the size of

microspheres. The mean particle size of the microballoons

significantly increased with increasing Eudragit S-100

concentration and was in the range of 268.6 ± 4.6 to

308.5 ± 2.4 mm (Table 1). Formulations were optimized in

terms of drug: polymer ratio; particle size of microballoon

ranged from 266.6 ± 4.3 to 302.8 ± 1.4 mm. Microballoons

was also optimized for varying emulsifier concentration

(% w/v). Mean particle size of microballoons was larger at

low concentration of emulsifier (0.5%; 293.7 ± 3.3 mm) and

it decreased with an increase in concentration of emulsifier

(1.25%; 249.6 ± 4.2 mm). An increase in stirring speed

(700 rpm) promoted formation of small sized microbal-

loons (274.6 ± 3.6). Table 2 demonstrates the optimized

formula.

Electron microscopy

Shape and surface morphology of microballoons was

observed by scanning electron microscopy (Figure 1) which

confirmed spherical shape and smooth surface of

microballoons.

Percent buoyancy

The buoyancy percentage for all batches almost was above

50% which was studied for 12 h.

In-vitro drug release study

In-vitro drug release studies were performed in simulated

gastric fluid pH 1.2 for 12 h. The in-vitro release profile was

biphasic with an initial burst release (16.05 ± 0.94%) upto

1.0 h which may be attributed to surface associated drug,

followed by a slower release phase as the entrapped drug

slowly diffused into the release medium (Figure 2).

Percentage of the drug released up to 12 h was 80.05 ± 0.64.

There was sustained release of drug at a constant rate.

In-vivo floating efficiency (X-ray) study

The optimized floating microspheres exhibited good in-vitro

buoyancy and controlled release behavior and hence was

finally selected for in-vivo radio graphical study. Examination

of the sequential X-ray images taken during the study clearly

indicates that the optimized formulation remained buoyant

Figure 1. SEM photomicrograph of nizatidine-loaded microballoons.

DOI: 10.3109/10717544.2014.891273 Nizatidine microballoons for gastric ulcers 3

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and uniformly distributed in the gastric contents for the study

period of 6 h (Figure 3).

Antiulcer activity

In ethanol-induced ulcer model, oral administration of 95%

ethanol in control group, produced characteristic lesions in

stomach which emerged as elongated bands of broad red

lesions. The in-vivo evaluation showed that UI values were

0.64 ± 0.08 for normal saline-treated group, 0.49 ± 0.11 for

nizatidine solution and 0.14 ± 0.08 for nizatidine microbal-

loons. Microballoons-treated group showed significant

(p50.01) ulcer protection index as compared to free drug-

treated group (Figure 4).

Discussion

Microballoons are one of the innovative gastroretentive drug

delivery systems. Their bulk density is less than density of

gastric contents which enables them to float in gastric fluid.

As microballoons float on gastric contents, drug is released at

a desired rate leading to maintenance of drug concentration

for a prolonged period of time. After the drug release is

completed, residual system is cleared off from the stomach.

Thus, such a system provides increased GRT and provides an

effective control over fluctuations in plasma drug

concentration.

Floating microballoons of nizatidine were prepared by

emulsion solvent diffusion method using Eudragit S-100 and

HPMC. Microballoons were prepared by using varying

concentration of Eudragit S-100 and fixed concentration of

HPMC. It is clear from Table 1 that formulation variables had

a great impact on buoyancy, particle size and entrapment

efficiency. On increasing Eudragit S-100 concentration, the

viscosity of the medium increased resulting in enhanced

interfacial tension. Shearing efficiency also diminished at

higher viscosities (Reddy et al., 1990). This resulted in

formation of larger sized particles.

Microballoons were prepared with different drug: polymer

ratio (1:1, 1:2, 1:3, 1:4), while other parameters were kept

constant. The mean particle size of the microballoons

increased significantly by decrease in drug polymer ratio.

The drug entrapment efficiency increased initially from

56.8 ± 3.6% to 68.2 ± 4.2% by the decrease in drug polymer

Figure 4. Evidence for the protective effect of nizatidine microballoons in rats treated with ethanol, (a) control group showing normal gastric integrity(b) nizatidine solution–treated group (100 mg/kg) (c) Nizatidine-loaded microballoons–treated group.

Figure 3. X-ray photographs of microballoons in the gastric region of rat after dosing of formulations in the fasted state: (a) before dosing, (b) 3 h afterdosing, (c) 6 h after dosing.

Figure 2. In-vitro release profile of optimized nizatidine microballoons(n¼ 3).

4 A. Jain et al. Drug Deliv, Early Online: 1–6

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ratio up to 1:3 after which it decreased. Since drug

entrapment, buoyancy and particle size are dependent on

factors like stirring speed and emulsifier concentration, an

increase in polymer concentration may have resulted in a shift

in the equilibrium between these factors, which was evident

by a reduction in drug entrapment and percentage buoyancy.

Thus, the optimized drug: polymer ratio was selected as 1:3.

The mean microballoon size, buoyancy and drug entrap-

ment efficiency were found to decrease with an increase in

emulsifier concentration. This may be due to the fact that

increase in emulsifier concentration resulted in increase in

miscibility of ethanol with dichloromethane (processing

medium), which may increase the extraction of drug into

the processing medium. The buoyancy could have decreased

due to tightening of polymeric network, leading to micro-

balloon shrinkage with an increase in concentration of

emulsifier. Increased degree of agitation (stirring) resulted

in formation of small sized microspheres.

Optimized formulation was subjected to in-vitro drug

release studies and floating behavior was observed by X-ray

studies. Shape of microballoons was examined by scanning

electron microscopy. Microballoons were distinguished as

spherical shape enfolded in hard polymer shell. Central cavity

of microballoons is formed due to volatilization of dichlor-

omethane. As the polymer and drug solution in dichloro-

methane and ethanol is dropped in PVA solution, ethanol

tends to diffuse in aqueous solution; this leads to formation of

a shell and produces a cavity within it which is produced due

to volatilization of dichloromethane. Such a phenomenon is

responsible for creating a buoyant and floating system that

tends to float in gastric fluid (Kawashima et al., 1991).

Buoyancy of microparticulate system is dependent on the

quantity of polymers, ratio of polymers and nature and type of

solvents used in formulation (Streubel et al., 2006). In the

current study, microballoons continuously floated over dis-

solution for more than 12 h. The buoyancy of microballoons

could be contributed due to presence of pores created due to

rapid evaporation of dichloromethane, by which air got

entrapped in pores allowing them to float.

Release of nizatidine from HPMC microballoons was

evaluated in SGF pH 1.2. A steady drug release (Figure 2)

from microballoons was observed, which could be due to

diffusion and erosion mechanism. This also demonstrated

‘‘no burst effect’’ from formulation as there was a progressive

drug release.

The success of any pharmaceutical formulation could be

assessed by biological studies. In the present work, ethanol-

induced ulcer model was utilized to determine efficacy of

nizatidine-loaded microballoons.

Ethanol produced gastric lesions which are due to stasis in

gastric blood flow which causes hemorrhage and tissue

necrosis. It rapidly penetrates gastric mucosa and plasma

membrane and enhances membrane permeability to water and

sodium which in turn augments massive calcium accumula-

tion. This proves to be a major step in pathogenesis of injury

of gastric mucosa (Halliwell & Gutteridge, 1987; Soll, 1990).

Along with it, when ethanol is metabolized in body, it causes

increased production of O�2 in tissues leading to increased

cellular free radical concentration, which are ultimately

responsible for breaking of DNA strands and protein

denaturation (Surendra, 1999). Nizatidine microballoons

efficiently inhibited ethanol-induced ulcers (Figure 4)

demonstrating its cytoprotective effect on gastric mucosa.

Conclusion

In-vitro data obtained for microballoons of nizatidine showed

excellent buoyancy. Microballoons of nizatidine floated in

SGF for a prolonged period of time and sustained drug release

from the beads over a period of 12 h. The in-vivo floating

efficiency of beads was satisfactory; beads were retained in

rat stomach for extended period. Thus, the microballoons may

prove to be promising candidate for obtaining stomach

specific drug delivery.

Acknowledgements

Authors are thankful to Rewa Shiksha Samiti for constant

support during studies.

Declaration of interest

The authors declare that there was no conflict of interest.

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