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ADVANCEMENT OF CHITOSAN-BASED NANOPARTICLES FOR

TARGETED DELIVERY OF ANTIULCER DRUGS

Devender Singh, Shashi Alok, Alok Mahor, Kaushal Kumar*

Institute of Pharmacy, Department of Pharmaceutics, Bundelkhand University, Jhansi

UP, India.

ABSTRACT

Chitosan nanoparticles have gained more attention as drug delivery

carriers because of their better stability, low toxicity, simple and mild

preparation method, and providing versatile routes of administration.

Their sub-micron size not only suitable for parenteral application, but

also applicable for mucosal routes of administration, i.e., oral, nasal,

and ocular mucosa, which are non-invasive route. Chitosan has

prompted the continuous movement for the development of safe and

effective drug delivery systems because of its unique physicochemical

and biological characteristics. The primary hydroxyl and amine groups

located on the backbone of chitosan allow for chemical modification to

control its physical properties. When the hydrophobic moiety is

conjugated to a chitosan molecule, the resulting amphiphile may form

self-assembled nanoparticles that can encapsulate a quantity of drugs and deliver them to a

specific site of action. Chemical attachment of the drug to the chitosan throughout the

functional linker may produce useful prodrugs, exhibiting the appropriate biological activity

at the target site.

KEYWORDS: Nanotechnology, Chitosan, Nanoparticles, promising drug carrier, Targeted

delivery.

INTRODUCTION

Nanotechnology can be defined as the science and engineering involved in the design,

synthesis, characterization and application of materials and devices whose smallest functional

organization is on the nanometer scale (one-billionth of a meter). [1-2]

It can prove to be a

boon for human health care, because nanoscience and nanotechnologies have a huge

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 2.786

Volume 4, Issue 1, 505-518. Review Article ISSN 2278 – 4357

Article Received on

23 Oct 2014,

Revised on 18 Nov 2014,

Accepted on 14 Dec 2014

*Correspondence for

Author

Kaushal Kumar

Institute of Pharmacy,

Department of

Pharmaceutics ,

Bundelkhand University,

Jhansi UP India.

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potential in the development of new and effective medical treatments. At present, 95% of all

new potential therapeutics have poor pharmacokinetics and biopharmaceutical properties.

Therefore, there is a need to develop suitable drug delivery systems that distribute the

therapeutically active drug molecule only to the site of action, without affecting healthy

organs and tissues. [3-5]

Nanotechnology plays an important role in therapies of the future as „nanomedicines‟, thus

lowering doses required for efficacy as well as increasing the therapeutic indices and safety

profiles of new therapeutics. We define nanomedicines as delivery systems in the nanometer

size range (preferably 1 to 100 nm) containing encapsulated, dispersed, adsorbed, or

conjugated drugs and imaging agents. Nanoscale drug delivery system also have the ability to

improve the pharmacokinetics and increase biodistribution of therapeutic agents to target

organs, which will result in improved efficacy and drug toxicity is also reduced as a

consequence of preferential accumulation at target sites and lower concentration in healthy

tissues. Functionalities can be added to nanomaterials by interfacing them with biological

molecules or structures. [6-8]

The size of nanomaterials is similar to that of most biological

molecules and structures; therefore, nanomaterials can be useful for both in vivo and in vitro

biomedical research and applications. Thus far, the integration of nanomaterials with biology

has led to the development of diagnostic devices, contrast agents, analytical tools, physical

therapy applications, and drug delivery vehicles. Nanotechnology is also opening up new

opportunities in implantable delivery systems, which are often preferable to the use of

injectable drugs, because the latter frequently display first order kinetics (the blood

concentration goes up rapidly, but drops exponentially over time). This rapid rise may cause

difficulties with toxicity, and drug efficacy can diminish as the drug concentration falls below

the targeted range. [9]

Controlled drug delivery technology represents one of the border areas of science, which

involves multidisciplinary scientific approach, contributing to human health care. The

concept of drug targeting and controlled drug delivery is used in attempts to improve the

therapeutic index of drugs by increasing thier localization to specific organs, tissues or cells

and by decreasing thier potential toxic side effects at normal sensitive sites. As in the field of

cancer therapy, chemotherapeutic agents have toxic side effects for tumor cells as well as for

normal cells; the controlled delivery of these agents to diseased sites would enable the use of

higher doses for increasing therapeutic efficacy. The advantages of using nanoparticles as a

drug delivery system include the following. [10]

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1. Particle size and surface characteristics of nanoparticales can be easily manipulated to

achieve both passive drug targeting after parenteral administration.

2. They control and sustain release of the drug during the transportation and at the side of

localization altering organ distribution of the drug and subsequent clearance of the drug

therapeutic efficacy and reduction in side effects.

3. Controlled release and particle degradation characteristics can be readily modulated by

the choice of matrix constituents. Drug loading is relatively high and drug can be

incorporated in to the system without any chemical reaction; this is an important factor

for preserving the drug activity.

4. Site-specific targeting can be achieved by attaching targeting ligands to surface of

particles use of magnetic guidance.

5. The system can be used for various routes of administration including oral, nasal,

parenteral, intra-ocural etc.

Polymer Used

Chitosan

Chitosan is a modified natural carbohydrate polymer prepared by the partial N-deacetylation

of chitin, a natural biopolymer derived from crustacean shells such as crabs, shrimps and

lobsters. Chitosan is also found in some microorganisms, yeast and fungi (Illum, 1998). [11]

The primary unit in the chitin polymer is 2-deoxy-2-(acetylamino) glucose. These units

combined by -(1,4) glycosidic linkages, forming a long chain linear polymer. Although

chitin is insoluble in most solvents, chitosan is soluble in most organic acidic solutions at pH

less than 6.5 including formic, acetic, tartaric, and citric acid (LeHoux and Grondin, 1993;

Peniston and Johnson, 1980). [12]

It is insoluble in phosphoric and sulfuric acid. Chitosan is

available in a wide range of molecular weight and degree of deacetylation. Molecular weight

and degree of deacetylation are the main factors affecting the particle size, particles formation

and aggregation. Chitosan is produced commercially by deacetylation of chitin, which is the

structural element in the exoskeleton of crustaceans (such as crabs and shrimp) and cell walls

of fungi. The degree of deacetylation (%DD) can be determined by NMR spectroscopy, and

the %DD in commercial chitosans ranges from 60 to 100%. On average, the molecular

weight of commercially produced chitosan is between 3800 and 20,000 Daltons. A common

method for the synthesis of chitosan is the deacetylation of chitin using sodium hydroxide in

excess as a reagent and water as a solvent. This reaction pathway, when allowed to go to

completion (complete deacetylation) yields up to 98% product.

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Chitin and chitosan have the same chemical structure. Chitin is made up of a linear chain of

acethylglucosamine groups. Chitosan is obtained by removing enough acethyl groups (CH3-

CO) for the molecule to be soluble in most diluted acids. This process, called deacetylation,

releases amine groups (NH) and gives the chitosan a cationic characteristic.

CHITIN CHITOSAN

The amino group in chitosan has a pKa value of ~6.5, which leads to a protonation in acidic

to neutral solution with a charge density dependent on pH and the %DA-value. This makes

chitosan water soluble and a bioadhesive which readily binds to negatively charged surfaces

such as mucosal membranes. Chitosan enhances the transport of polar drugs across epithelial

surfaces, and is biocompatible and biodegradable. It is not approved by FDA for drug

delivery though. Purified quantities of chitosan are available for biomedical applications. [13]

Drug Used

H2 Receptor Antagonists

The major, most potent and effective antiulcer medications are the selective histamine type 2

receptor blockers (H2 blockers) and the proton pump inhibitors (PPIs). Both classes of

antiulcer medications block the pathways of acid production or secretion, decreasing gastric

acidity, improving symptoms and aiding in healing of acid-peptic diseases. These are some

of the most commonly used drugs in medicine and are generally well tolerated and rarely

result in serious adverse events. Nevertheless, both of these classes of agents have been

linked to rare instances of acute liver injury and are discussed in LiverTox. [14]

The antiulcer agents in clinical use that are discussed in LiverTox include the following:

Selective Histamine Type 2 Receptor Antagonists/Blockers

a) Cimetidine

b) Famotidine

c) Nizatidine

d) Ranitidine

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Proton Pump Inhibitors

a) Esomeprazole

b) Lansoprazole

c) Omeprazole

d) Pantoprazole

e) Rabeprazole

Cimetidine: Cimetidine inhibits cytochrome P-450 and reduces hepatic blood flow.

Cimentidine is a competitive histamine H2-receptor antagonist whose effects include

inhibition of gastric acid secretion and reduction of pepsin output. Cimeditine has been used

in the culture of rabbit gastric parietal cells for subsequent ultrastructural examination.

Cimetidine blocks the histamineinduced surface expression of P-selectin in primary cultured

human brain microvessel endothelial cells. A study of cultured human monocytes has utilized

cimetidine to probe the expression of histidine decarboxylase. The susceptibility of

cimetidine to metabolism by colonic bacteria in vitro has been investigated. [15]

Famotidine: Famotidine is a histamine type 2 receptor antagonist (H2 blocker) which is

commonly used for treatment of acid-peptic disease and heartburn. Famotidine has been

linked to rare instances of clinically apparent acute liver injury. The H2 blockers are specific

antagonists of the histamine type 2 receptor, which is found on the basolateral (antiluminal)

membrane of gastric parietal cells. The binding of famotidine to the H2 receptor results in

inhibition of acid production and secretion, and improvement in symptoms and signs of acid-

peptic disease. The H2 blockers inhibit an early, “upstream” step in gastric acid production

and are less potent that the proton pump inhibitors, which inhibit the final common step in

acid secretion. Famotidine is metabolized by the hepatic cytochrome P450 system but has

minimal inhibitory effects on the metabolism of other drugs, making it less likely to cause

drug-drug interactions than cimetidine. [16]

Nizatidine: 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 used to treat certain conditions

caused by too much acid being produced in the stomach, such as stomach ulcers (gastric

ulcers), ulcers of the upper part of the intestine (duodenal ulcers), acid reflux or heartburn

(reflux oesophagitis), and indigestion. It can also be used to treat irritation and ulceration of

the stomach which has been caused by non-steroidal anti-inflammatory drugs (NSAIDs). [17]

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Ranitidine: Ranitidine is a histamine H2-receptor antagonist which reduces the amount of

stomach acid produced and thus prevents reflux causing inflammation in the oesophagus, and

also allows existing inflammation to heal. It does not decrease the amount of spilling or

vomiting. It may take from a few days to a few weeks to see an improvement in your

baby/child after starting Ranitidine. The dosage may need adjusting for weight as the baby

grows. Ranitidine syrup contains ethanol (alcohol) and was not formulated for paediatric use.

It has however been used successfully in the treatment of reflux in children for many years.

[18]

Esomeprazole: Esomeprazole is a weak base, which is converted to its active form in the

acidic environment of the gastric parietal cell. Like other PPIs, esomeprazole inhibits basal

and stimulated acid secretion by binding to the H+/K+-ATPase enzyme in the parietal cell.

Esomeprazole is the S-isomer of omeprazole. The range of licensed indications for

esomeprazole is more limited than that for omeprazole and excludes prevention and treatment

of NSAID-associated gastric and duodenal ulceration, healing of gastric/duodenal ulcers

other than duodenal ulcers associated with H. pylori, and Zollinger-Ellison syndrome. [19-20]

Lansoprazole: Lansoprazole belongs to a class of antisecretory compounds, the substituted

benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H, K)-

ATPase++

enzyme system at the secretory surface of the gastric parietal cell. Because this

enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole

has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid

production. This effect is dose-related and leads to inhibition of both basal and stimulated

gastric acid secretion irrespective of the stimulus. Lansoprazole does not exhibit

anticholinergic or histamine type-2 antagonist activity.

Omeprazole: Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia,

peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD) and Zollinger-

Ellison syndrome. Proton pump inhibitors act by irreversibly blocking the

hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or more

commonly just gastric proton pump) of the gastric parietal cell. The proton pump is the

terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into

the gastric lumen, making it an ideal target for inhibiting acid secretion. [21]

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Pantoprazole: Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in

gastric acid production by covalently binding to the (H+, K+)-ATPase enzyme system at the

secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and

stimulated gastric acid secretion, irrespective of the stimulus. The binding to the (H+, K+)-

ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all

doses tested (20 mg to 120 mg).

Rabeprazole: Rabeprazol is an antiulcer drug in the class of proton pump inhibitors. Which

used in healing and symptomatic relief of duodenal ulcers and erosive or ulcerative

gastroesophageal reflux disease (GORD); maintaining healing and reducing relapse rates of

heartburn symptoms in patients with GORD; treatment of daytime and nighttime heartburn

and other symptoms associated with GORD; long-term treatment of pathological

hypersecretory conditions, including Zollinger-Ellison syndrome and in combination with

amoxicillin and clarithromycin to eradicate Helicobacter pylori.

Methods

Methods for preparation of nanoparticles: Mainly four methods are well known for the

preparation of chitosan nanoparticles.

1. Ionotropic gelation method.

2. Microemulsion method.

3. Emulsification solvent diffusion method.

4. Polyelectrolyte complex formation.

Ionotropic Gelation Method

Some of the natural macromolecules have been used to prepare NPs. These polymers include

gelatin, alginate, chitosan and agarose. They are hydrophilic natural polymers and have been

used to synthesize biodegradable NPs by the ionic gelation method. This involves the

transition of materials from liquid to gel due to ionic interaction at room temperature. An

example of preparation of gelatin NPs includes hardening of the droplets of emulsified

gelatin solution into gelatin NPs. The gelatin emulsion droplets are cooled below the gelation

point in an ice bath leading to gelation of the droplets into gelatin NPs. Alginate NPs are

reported to be produced by drop-by-drop extrusion of the sodium alginate solution into the

calcium chloride solution. Sodium alginate is a water-soluble polymer that gels in the

presence of multivalent cations such as calcium. Chitosan NPs are prepared by spontaneous

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formation of complexes between chitosan and polyanions or by the gelation of a chitosan

solution dispersed in an oil emulsion. [22-23]

(Fig-no1)

Fig 1: Schematic representation of ionic gelation method.

Emulsification Solvent Diffusion Method

This is a modified solvent diffusion method where a water-miscible solvent such as acetone

or methanol along with a water-insoluble organic solvent such as dichloromethane or

chloroform are used as an oil phase. Due to the spontaneous diffusion of solvents, an

interfacial turbulence is created between the two phases leading to the formation of smaller

particles. As the concentration of water- soluble solvent increases, smaller particle sizes of

NPs can be achieved. [24-26]

(Fig-2)

Fig 2: Schematic representation of the emulsification/solvent diffusion technique.

Micro-Emulsion Method

Chitosan NP prepared by microemulsion technique was first developed by Maitra et al. This

technique is based on formation of chitosan NP in the aqueous core of reverse micellar

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droplets and subsequently cross-linked through glutaraldehyde. In this method, a surfactant

was dissolved in N-hexane. Then, chitosan in acetic solution and glutaraldehyde were added

to surfactant/hexane mixture under continuous stirring at room temperature. Nanoparticles

were formed in the presence of surfactant. The system was stirred overnight to complete the

cross-linking process, which the free amine group of chitosan conjugates with

glutaraldehyde. The organic solvent is then removed by evaporation under low pressure. The

yields obtained were the cross-linked chitosan NP and excess surfactant. The excess

surfactant was then removed by precipitate with CaCl2 and then the precipitant was removed

by centrifugation. The final nanoparticles suspension was dialyzed before lyophilyzation.

This technique offers a narrow size distribution of less than 100 nm and the particle size can

be controlled by varying the amount of glutaraldehyde that alter the degree of cross-linking.

Nevertheless, some disadvantages exist such as the use of organic solvent, time-consuming

preparation process, and complexity in the washing step. [27-28]

Polyelectrolyte Complex (PEC) Method

Polyelectrolyte complex or self assemble polyelectrolyte is a term to describe complexes

formed by self-assembly of the cationic charged polymer and plasmid DNA. Mechanism of

PEC formation involves charge neutralization between cationic polymer and DNA leading to

a fall in hydrophilicity. Several cationic polymers (i.e. gelatin, polyethylenimine) also possess

this property. Generally, this technique offers simple and mild preparation method without

harsh conditions involved. The nanoparticles spontaneously formed after addition of DNA

solution into chitosan dissolved in acetic acid solution, under mechanical stirring at or under

room temperature. The complexes size can be varied from 50 nm to 700 nm. [29-30]

Characterization of Particles

Fourier Transform Infrared Spectrometry (FT-IR)

FT-IR spectra were recorded with a Nicolet 60-SXB spectrometerin the range of 400-4000

cm-1

using a resolution of 4 cm-1

and 10 scans, to evaluate the molecular states of micronized

and nano-formulations of drugs. Samples were mixed with potassium bromide (KBr) and

were pressed to obtained supporting disks.

X-ray Diffraction(XRD)

The physical state of nanoformulation was studied by means of XRD patterns (Shimadzu

XRD-6000, Mumbai, India). Phase identification was conducted using an X-ray powder

diffractometer with Cu Ka radiation (lemda=1.5A0

, filter- Ni, voltage- 40K, time constant- 5

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mm/sec, scanning rate- 10/min). Data is collected at 20 from ~0

0 to 40

0, angles that are preset

in the X-ray scan.

Size and Surface Morphology

The particle morphology was examined by transmission electron microscope (TEM; Zeiss

EM 10 CR, Germany). Different drops of the solution were applied to Formvar-coated grid

and left to dry at room temperature to be studied under the TEM. Different particle size was

observed and the photograph was taken for a representative sample. The particle size

distribution of the resulted particles was determined with Zetasizer Nano ZS (Malvern

Instruments, UK) at 25°C. The angle of the scattering light used for particle size

determination was 173o. Sample analysis was based on water viscosity (0.88 mPa s) and

refractive index (1.33) at 25°C. Solution containing particles were diluted 1:10 v/v with pure

deionized water, simulated gastric fluid (SGF), or simulated intestinal fluid (SIF) and samples

were measured for three times and 11 reading per run. The average hydrodynamic diameter

was determined automatically.

Drug particles in the nanometer size range have unique characteristics that can lead to

enhanced performance in a variety of dosage forms. Formulated correctly, particles in this

size range are resistant to settling and can have higher saturation solubility, rapid dissolution,

and enhanced adhesion to biological surfaces, thereby providing a rapid onset of therapeutic

action and improved bioavailability. Pharmaceutical nanoparticles are subnanosize structure,

which contain drug or bioactive substances with in them and are constituted of several tens or

hundreds of atoms or molecules with a variety of sizes (size from 5 nm to 300 nm) and

morphologies (amorphous, crystalline, spherical, needles, etc).

Zeta Potential

The zeta potential was measured with Zetasizer Nano ZS (Malvern Instrument, UK) at 25°C.

The preparation was diluted 1:10 v/v with pure deionized water, SGF, or SIF. The viscosity

and dielectric constant of pure water were used for Zeta potential calculation. Samples were

diluted in a similar fashion as that described above for the particle size distribution. All

measurement were made in triplicate and the mean values and standard deviations were

reported.

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Encapsulation Efficiency

The method of determination of the amount of drug entrapped within nanoparticles has been

described in a previous work. Briefly, the nanoparticles were centrifuged at 15,000 rpm for

30 min at 15°C and the drug content in the supernatant was assayed by reversed-phase high-

pressure liquid chromatography (RP-HPLC).

Nanoparticle Recovery

The nanoparticle (NP) recovery; which is referred to as nanoparticle yield in the literature,

calculated using Eq. given below. The individual values were determined.

Nanoparticle recovery (%)= (Mass of nanoparticles recovered*100/Mass of polymeric

nanoparticles with drug).

Drug Loading and Loading Efficiency

Although drug loading expresses the percent weight of active ingredient encapsulated to the

weight of nanoparticles, drug loading efficiency is the ratio of the experimentally determined

percentage of drug content compared with actual, or theoretical mass of drug used for the

preparation of the nanoparticles. The loading efficiency depends on the polymer-drug

combination and the method used. Hydrophobic polymers encapsulate large amounts of

hydrophobic drugs, whereas hydrophilic polymers entrap greater amounts of more

hydrophilic drugs.

In - Vitro Release Study

The in vitro release of nanoparticles was carried out in triplicate in stirred dissolution cells at

37.40C by suspending 2 ml of nanoparticle suspension into a beaker containing 100 ml of

release media (phosphate buffer saline pH 7.5). The correct in vitro conditions to study the

release behaviour of a hydrophobic drug were maintained. Drug release was assessed by

intermittently sampling the receptor media (5 ml) at predetermined time intervals, each time 5

ml of fresh phosphate buffer saline pH 7.4 was replaced. The amount of repaglinide release in

the buffer solution was quantified by suitable assay technique.

CONCLUSION

The development of nanoparticles represents a significant advance over the conventional

vesicular systems. This concept of incorporating the drug into nanoparticles for a better

targeting at appropriate tissue destination and for controlled delivery is widely accepted by

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researchers. As a drug delivery device, nanoparticles are osmotically active and stable.

Nanoparticles are thought to be better candidates of drug delivery as compared to liposomes

and niosomes due to various factors like cost, stability etc. Compared to liposome or

niosomes, proniosomes are very promising as drug carriers and compared to liposome and

niosome suspension, proniosome represents a significant improvement by eliminating

physical stability problems, such as aggregation or fusion of vesicles and leaking of

entrapped drug‟s during long term storage. Nanoparticles are convenient to store, transport

and for unit dosing since nanoparticles have similar release characteristics as conventional

niosomes, it may offer improved bioavailability of some drugs with poor solubility controlled

release formulations or reduced adverse effects of some drugs. The slurry method was found

to be simple and suitable for laboratory scale preparation of nanoparticles.

ACKNOWLEDGMENT

The authors are thankful to Prof. Dr. S.K. Prajapati (H.O.D, Institue of Pharmacy,

Bundelkhand University, Jhansi UP, India) and Mr. Devender Singh (Asst. Prof.

Pharmaceutics, Institute of Pharmacy, B.U, Jhansi UP) for their technical assistance in

carrying out only for review article.

Source of Support: Nil; Conflict of interest: None declared.

REFERENCES

1. Emerich D.F., Thanos C.G.: Nanotech and medicin, Expert OpinBiolTher, 2003; 3: 655-

663.

2. Sahoo S.K., Labhasetwar V.: Nanotech approaches to drug delivery and imaging, Drug

Discov Today, 2003; 8: 1112-1120.

3. Williams D.: Nanotechnology: a new look, Med Device Technol. 2004, 15, 9-10.

4. Chan W.C.: Bionanotechnology progress and advances, Biol Blood Marrow Transplant,

2006; 12: 87-91.

5. Rubin R, Peyrot M, Kruger D, Travis L. Barriers to insulin injection therapy: patient and

health care provider perspectives. Diabetes Educ. 2009;35:1014–22. doi:

10.1177/0145721709345773.

6. Au J.L et al: Determination of drug delivery and transport to solid tumors, J Control

Release, 2001; 74: 31-46.

7. Fetterly G.J., Straubinger R.M.: Pharmacokinetics of paclitaxel containing liposomes in

rats, AAPS Pharm Sci, 2003; 5: E32.

www.wjpps.com Vol 4, Issue 1, 2015.

517

Kaushal et al. World Journal of Pharmacy and Pharmaceutical Sciences

8. Hoarau D., Delmas P., David S., Roux E., Leroux J.C.: Novel long circulating lipid

nanocapsules, Pharm Res, 2004; 21: 1783-1789.

9. Moghimi S.M., Szebeni J.L.: Stealth liposomes and long circulating nanoparticles: critical

issues in pharmacokinetics, opsonisation and protein-binding properties, Prog Lipid Res,

2003; 42: 463-478.

10. Niwa T, Takeuchi H, Hino T, Kunou N, Kawashima Y. Preparation of biodegradable

nanoparticles of water-soluble and insoluble drugs with D, Llactide/ glycolide copolymer

by a novel spontaneous emulsification solvent diffusion method, and the drug release

behavior. J. Control.Release, 1993; 25: 89-98.

11. Illum, L. 1998. Chitosan and its use as a pharmaceutical excipient. Pharm. Res, 15: 1326-

1331.

12. LeHoux, J. G., and F. Grondin. 1993. Some effects of chitosan on liver function in the rat.

Endocrinology 132: 1078-1084.

13. Nagamoto T, Hattori Y, Takayama K, et al. Novel chitosan particles and chitosan-coated

emulsions inducing immune response via intranasal vaccine delivery. Pharm Res, 2004;

21: 671–674. doi: 10.1023/B:PHAM.0000022414.17183.58.

14. DiMario F, Battaglia G, Saggioro A, et al. H2 antagonists and gastric ulcer: A

multicenter, randomized, double-blind, controlled study comparing nizatidine with

ranitidine. Curr Ther Res, 1993; 54: 572-579.

15. Cimetidine [package insert]. Weston, FL; Apotex; August 2005.

16. Mota AP, Plaza Ag, Rodrigo M, et al. Famotidine versus cimetidine in the treatment of

benign gastric ulcers. Curr Ther Res, 1990; 47: 814-819.

17. Cherner JA, Cloud ML, Offen WW, et al. Comparison of nizatidine and cimetidine as

once-nightly treatment of acute duodenal ulcer. Nizatidine Multicenter Duodenal Ulcer

Study Group. Am J Gastroenterol, 1989; 84(7): 769-774.

18. DiMario F, Battaglia G, Saggioro A, et al. H2 antagonists and gastric ulcer: A

multicenter, randomized, double-blind, controlled study comparing nizatidine with

ranitidine. Curr Ther Res, 1993; 54: 572-579.

19. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association

medical position statement on the management of gastroesophageal reflux disease.

Gastroenterology, 2008; 135(4): 1383-91.

20. Lind T et al. Esomeprazole provides improved acid control vs omeprazole in patients with

symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Ther, 2000; 14: 861-

867.

www.wjpps.com Vol 4, Issue 1, 2015.

518

Kaushal et al. World Journal of Pharmacy and Pharmaceutical Sciences

21. Richter JE et al. Esomeprazole is superior to omeprazole for the healing of erosive

esophagitis in GERD patients. Gastroenterology, 2000; 118 (4; suppl 2): A343.

22. Calvo P, Remunan-Lopez C, Vila-Jato JL, Alonso MJ. Novel hydrophilic chitosan-

polyethylene oxide nanoprticles as protein carriers. J. Appl. Polymer Sci, 1997; 63: 125-

132.

23. Amir Dustgania, Ebrahim Vasheghani Farahania, Mohammad Imanib. Preparation of

Chitosan Nanoparticles Loaded by Dexamethasone Sodium Phosphate. Iranian J Pharma

Sci, 2008, 4(2): 111-114.

24. Niwa T, Takeuchi H, Hino T, Kunou N, Kawashima Y. Preparation of biodegradable

nanoparticles of water-soluble and insoluble drugs with D, Llactide/ glycolide copolymer

by a novel spontaneous emulsification solvent diffusion method, and the drug release

behavior. J. Control.Release, 1993; 25: 89-98.

25. Vargas A, Pegaz B, Debefve E, Konan-Kouakou Y, Lange N, Ballini JP. Improved

photodynamic activity of porphyrin loaded into nanoparticles: an in vivo evaluation using

chick embryos. Int J Pharm, 2004; 286:131- 45.

26. Yoo HS, Oh JE, Lee KH, Park TG. Biodegradable nanoparticles containing PLGA

conjugate for sustained release. Pharm Res, 1999; 16:1114- 8.

27. Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by

interfacial deposition following solvent displacement. Int J Pharm, 1989, 55: R1- R4.

28. Puig JE. Microemulsion polymerization (oil-in water). In: Salamone JC, editor. Polymeric

materials encyclopedia, (6) Boca Raton, FL: CRC Press, 1996; 4333–41.

29. Nicolas J, Charleux B, Guerret O, Magnet S. Nitroxide-mediated controlled free-radical

emulsion polymerization using a difunctional water-soluble alkoxyamine initiator.

Toward the control of particle size, particle size distribution, and the synthesis of tri block

copolymers. Macromolecules, 2005; 38: 9963–73.

30. Farcet C, Lansalot M, Charleux B, Pirri R, Vairon JP. Mechanistic aspects of nitroxide-

mediated controlled radical polymerization of styrene in miniemulsion, using a water-

soluble radical initiator. Macromolecules, 2000; 33: 8559–70.