10. Review of Literature - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/19935/1/10. review of literature.pdf2. REVIEW OF LITERATURE 2.1. Based on colon specific drug delivery

Chapter 2 Review of Literature

School of Pharmaceutical Sciences 21

2. REVIEW OF LITERATURE

2.1. Based on colon specific drug delivery system

2.1.1. Mahale et al., 2013 have studied the colon specific delivery systems. The colonic

environment in the lower GIT has attained important value in the design of colon targeted drug

delivery systems. Targeted drug delivery into colon is highly recommended for local treatment of

a variety of bowel diseases like ulcerative colitis, Crohn’s disease, amebiosis, colonic cancer etc.

Mechanisms of drug targeting to the colon are pH-dependent delivery, time-dependent delivery,

pressure-dependent delivery and bacteria dependent delivery etc.

2.1.2. Srivastava et al., 2012 have developed calcium-pectinate matrix tablet for colon-targeted

delivery of meloxicam (MLX) microsponges. Modified Quassi-emulsion solvent diffusion

method was used to formulate microsponges (MS). The effects of volume of dichloromethane

and Eudragit RS100 content (independent variables) were determined on the particle size,

entrapment efficiency and %cumulative drug release of MS1–MS9. The optimized formulation

was developed into colon-targeted matrix tablet using calcium pectinate as the matrix. The

optimized colon-targeted tablet shielded MLX loaded microsponges in gastrointestinal region

and selectively delivered them to colon, as visualized by vivo fluoroscopy in rabbits. The

pharmacokinetic evaluation in rabbits, revealed drug in plasma after a lag time of 7 h, a tmax of 30

h with Fr = 61.047%, thus presenting a formulation suitable for targeted colonic delivery.

Calcium pectinate matrix tablet loaded with MLX microsponges were developed as a promising

system for the colon-specific delivery.

2.1.3. Pandey et al., 2012 have worked on tinidazole microbeads for colon targeting. The

objective of study was to develop and evaluate multiparticulate system exploiting pH-sensitive

property and specific biodegradability of calcium alginate microbeads, for colon- targeted

delivery of tinidazole for the treatment of amoebic colitis. The calcium alginate beads containing

tinidazole were prepared by ionotropic gelation technique followed by coating with Eudragit

S100 using solvent evaporation method to obtain pH sensitive microbeads. Various formulation

parameters were optimized which included concentration of sodium alginate (2% w/v), curing

time (20 min) and concentration of pectin (1% w/v). All the formulations were evaluated for

surface morphology, particle size analysis, entrapment efficiency and in-vitro drug release in



conditions simulating colonic fluid in the presence of rat caecal (2% w/v) content. The result

showed that average size of beads of optimized formulation (FT4) was found to be 998.73 ±5.12

µm with entrapment efficiency of 87.28±2.19 %. The in-vitro release of Eudragit S100 coated

beads in presence of rat caecal content was found to be 70.73%± 1.91% in 24 hours. Data of in-

vitro release was fitted into Higuchi kinetics and Korsmeyer Peppas equation to explain release

profile. The optimized formulation (FT 4) showed zero order release.

2.1.4. Mura et al., 2012 have worked on 5- aminosalicyclic acid N- succinyl- chitosan

microparticles for colon specific delivery. The objective of study was to prepare NS-chitosan

microparticles for the delivery of 5-aminosalicylic acid (5-ASA) to the colon. N-Succinyl-

chitosan was chosen as carrier system because it has excellent pharmaceutical properties in colon

drug targeting such as poor solubility in acid environment, biocompatibility, mucoadhesive

properties, and low toxicity. 5-ASA loaded NS-chitosan microparticles were prepared using

spray-drying method. As a control, a matrix obtained by freeze-drying technique was also

prepared and evaluated. The result showed that mean size of the microparticles was around 5µm.

SEM images showed an acceptable spherical non porous structure of microparticles. In-vitro

swelling and drug release studies were in accordance with the polymer properties, showing the

highest swelling ratio and drug release at pH = 7.4 (colonic pH) where microparticles were able

to deliver more than 90% of 5-ASA during 24 h.

2.1.5. Juan et al., 2012 have prepared azo- reductase activated budesodine prodrugs for colon

targeting. The objective of present study was to produce local topical effect, improving safety

and increasing anti-inflammatory efficacy. The budesodine prodrug were synthesized and tested

using an in-vitro azo reductase assay simulating human colonic microflora. The kinetics of

amino steroid ester cyclization and its pH dependence was also evaluated. The result showed that

prodrug of budesodine was potential in management of ulcerative colitis.

2.1.6. Sirisha et al., 2012 have developed colon targeting mesalamine matrix tablet. The

objective of present study was to deliver tablet directly into the colon by using both hydrophilic

and hydrophobic polymers. Matrix tablets were prepared by direct compression method using

different concentration of HPME and EC. Evaluation like hardness, friability, weight variation,

thickness and drug content of prepared formulations were done. The results showed that

combination of both polymers exhibit best release profile and able to sustain the drug release for

prolong period of time. The test batch comparison analysis was conformed that combination of



both hydrophilic and hydrophobic polymer successfully employed for formulating the sustain

release colon targeted matrix tablet of mesalamine.

2.1.7. Mishra et al., 2012 have synthesized and characterized amino acid conjugate of naproxen.

The objective of work was to enhance the solubility without affecting permeability and deliver

naproxen to colon without significant reversion of prodrug in gastrointestinal conditions. The

naproxen- glycine conjugate was prepared by conventional coupling method and prodrug was

characterized by FTIR, FTNMR, FABMS, and element analysis. The results showed that

prodrug possessed therapeutically efficacious drug delivery system with less pharmaceutical

limitations.

2.1.8. Nangude et al., 2012 have studied colon targeted oral matrix tablets of naproxen and

esomeprazole. The objective of this study was to develop colon targeted drug delivery system of

naproxen and esomeprazole using different polymers for treatment of IBD. In this, matrix tablet

was prepared and various evaluation tests were carried out. Maximum drug release occurred in

phosphate buffer (pH 6.8). The results showed that optimized formulation showed no change

either in physical appearance, drug content or dissolution pattern after storage at 40 ̊C/ 75% RH

for three months.

2.1.9. Sarkar et al., 2011 had investigated prednisolone tablets for colon targeting delivery

system. The prednisolone tablets were prepared using wet granulation method with various

additive and coating. Different concentration of avicel and PVP were used; acted as canalizing

and binding agent. The results showed that lactose as diluents provided reasonable release for

prednisolone among other diluents. The 1% Eudragit RS showed 100% release of drug in

comparison with other concentration. 10% PVP gave the best results. The prednisolone modified

release tablet was successfully formulated using wet granulation method as a potential colon

delivery system.

2.1.10. Potu et al., 2011 have studied on fenoprofen calcium compressed coated tablets for colon

specific drug delivery. The main objective of study was to release the drug maximum in targeted

area i.e. physiological environment of colon. Various formulations were prepared using different

ratio of guar gum and HPMC. HPMC was included in this study to control the solubility of guar

gum and to prevent premature drug release in stomach and small intestine. Dissolution studies in

pH 6.8 phosphate buffer were carried out. The results of in-vitro study indicated the formulation

containing 60% guar gum was able to release less than 1% of drug in environment of stomach



and small intestine while 98% release of drug in targeted area. In vivo X-ray study showed that

design dosage form reaches the targeted site.

2.1.11. Yadav et al., 2011 have prepared polymeric prodrug of 4- aminosalicyclic acid for

inflammatory bowel disease. The objective of work was to reduce the frequency of

administration and avoid the gastrointestinal adverse effects associated with 4-ASA. The

synthesized prodrug was characterized by melting point, Rf value, FT-IR and 1H NMR. In-vitro

drug release was conducted at pH 1.2, 7.4 and in presence of rat faecal matter (pH 7.4). The

results showed that maximum 92.8% of drug release from prodrug and time taken for 50% drug

release was found to be nearly 3.5 hours. The amount of 4- aminosalicyclic acid released in

colon was found to be very high as compared to stomach and intestine.

2.1.12. Trombino et al., 2011 have synthesized lysine based prodrug of 5- Aminosalicyclic acid

and 6- Mercaptopurine for colon specific release. The aim of work was to design and

characterization of prodrug for the colon targeting. In this, prodrugs were synthesized and

characterized by FT-IR, 1H NMR and GC/ MS spectroscopy. The results suggested that the

prodrug could have high potential in tumors treatment, targeting 6-MP to the colon and

outweighing the disadvantage occur with the conventional treatment system.

2.1.13. Dube et al., 2011 have developed colon targeted lornoxicam matrix tablet. The objective

of study was to target drug directly to the colon and reducing systemic side effect. Matrix tablets

were prepared by direct compression method using different concentration of HPMC and EC.

Evaluation like hardness, friability, thickness, % drug content, weight variation and in-vitro

study of prepared formulation was done. The results showed that combination of both polymers

exhibit best release profile and able to sustain the drug release for prolong period of time.

2.1.14. Jose et al., 2011 have developed colon-specific chitosan microspheres for chronotherapy

of chronic angina. Chitosan microspheres were formulated by emulsion cross-linking method

and tested for chronotherapy of chronic stable angina. Diltiazem hydrochloride was encapsulated

in the chitosan microspheres following coating with Eudragit S-100 by solvent evaporation

technique, exploiting the advantages of microbiological properties of chitosan and pH dependent

solubility of Eudragit S-100. Different microsphere formulations were prepared by varying the

ratio diltiazem hydrochloride: chitosan. The effects of these variables on the particle size and

encapsulation parameters were evaluated to develop an optimized formulation. In-vitro release

study of non-coated chitosan microspheres in simulated gastrointestinal (GI) fluid exhibited a



burst release while Eudragit coated microspheres showed release at colonic pH. Chitosan

biodegradability was proved by the enhanced release rate of diltiazem hydrochloride in presence

of rat caecal contents.

2.1.15. Kothawade et al., 2011 have studied conventional and novel approaches for colon

specific drug delivery. Colon specific drug delivery is not only useful for targeting the drugs

required in the treatment of diseases associated with colon, but also as a potential site for the

local and systemic delivery of peptide and proteins and other therapeutic drugs. Precise colon

drug delivery requires the triggering mechanism in the delivery system that can respond only to

the physiological conditions specific to the colon. The primary approaches used to obtain colon-

specific delivery were based on prodrugs, pH and time dependent systems or microflora

activated systems. Recently continuous efforts have been taken on designing colon-specific

delivery systems with improved site specificity and versatile drug release kinetics to accomplish

different therapeutic needs. Different studies provided detailed insight into the conventional as

well as recent approaches used to target the therapeutic agents specifically to the colon.

2.1.16. Challa et al., 2011 have studied novel approaches on colon specific drug delivery. Colon

specific drug delivery has gained increased importance not just for delivery of the drugs in the

treatment associated with the colon, but also as a potential site for the systemic delivery of

therapeutic peptides and proteins. To achieve successful colon targeted drug delivery, a drug

need to be protected from degradation, release and absorption in the upper portion of the GI tract

and then to be ensured abrupt or controlled release in the proximal colon.

2.1.17. Philip et al., 2010 have studied primary and novel approaches for colon targeted drug

delivery system. The colon is a site where both local and systemic delivery of drugs can take

place. Local delivery allows topical treatment of inflammatory bowel disease. However,

treatment can be made effective if the drugs can be targeted directly into the colon, thereby

reducing the systemic side effects.

2.1.18. Patel et al., 2010 have studied enteric coated tablets of prednisolone for colon targeted

drug delivery. The main objective of this study was to reduce the frequency of dose

administration, prevent ulcerative colitis and also reduce the side effect of anti-inflammatory

drug in GI tract by developing delay release (DR) tablet of prednisolone using Eudragit S 100 as

enteric coating. The matrix tablet of prednisolone tablet was formulated by wet granulation

method. In-vitro drug release was performed by using simulating colonic fluid of pH 7.4 as



dissolution media. The results showed that Eudragit S100 can successfully be used to coat the

tablets for colon targeted delivery of drug.

2.1.19. Udo et al., 2010 have worked on 5- Fluorouracil acetic acid/ β- cyclodextrin conjugates:

Drug release behavior in enzymatic and rat caecal media. In this, 5- fluorouracil-1- acetic acid

was prepared and covalently conjugated to β- cyclodextrin through ester o amide linkage. The

drug release behavior of the conjugates in enzymatic solution and rat caecal contents were

investigated. The 5-FUA/β-CyD ester conjugate was slowly hydrolyzed to 5-FUA in aqueous

solutions, whereas the amide conjugate was hardly hydrolyzed at these physiological conditions,

but hydrolyzed only in strong alkaline solutions (>0.1MNaOH) at 60 ̊C, both ester and amide

conjugates were degraded in solutions of a sugar-degrading enzyme, α-amylase to 5-

FUA/maltose and triose conjugates, but the release of 5-FUA was only slight in α-amylase

solutions. In solutions of an ester-hydrolyzing enzyme carboxylic esterase, the ester conjugate

was hydrolyzed to 5-FUA at the same rate as that in the absence of the enzyme, whereas the

amide conjugate was not hydrolyzed by the enzyme. The results indicated that the ester

conjugate was hydrolyzed to 5- FUA. The in-vitro release behavior of the ester conjugate was

clearly reflected in the hydrolysis in rat caecal contents and in the in vivo release after oral

administration to rats.

2.1.20. Philip et al., 2009 have worked on colon targeting drug delivery system. Prodrug was

synthesizing by coupling ketoprofen with glycine. Reversion of KET- GLY to ketoprofen was

carried out at different pH and at pH 6.8 containing rat faecal contents. In-vitro reversion study

showed that KET- GLY remained intact in stomach but released the free drug at pH 6.8

containing fresh faecal material. In vivo study showed that KET- GLY was less toxic in stomach

with enhanced anti-inflammatory potential in the colonic region. KET- GLY was better in action

as compared with the parent drug.

2.1.21. Varshosaz et al., 2009 have worked on colon specific delivery system of budesonide to

increase the efficacy in the treatment of ulcerative colitis. The main objective of study was to

prepare Dextran- budesonide conjugates with different molecular weight of dextran (10,000,

70,000 and 500,000) in the presence of dimethylaminopyridine using succinate spacer.

Conjugate prepared by dextran 70,000 showed the most desirable solubility, stability and release

properties. In vivo evaluation was carried out to analyze potential clinical use in the treatment of

ulcerative colitis.



2.1.22. Makhlof et al., 2009 have design pH- sensitive nanospheres for colon - specific drug

delivery in experimentally induced colitis rat model. Nanospheres were prepared using

polymeric mixture of poly (lactic-co-glycolic) acid and pH sensitive methacrylate copolymer.

Budesonide, active corticosteroid, was entrapped as a model drug. The therapeutic efficacy of the

prepared nanospheres was assessed using the TNBS (Trinitrobenzene sulfonate) colitis in rat, in

comparison with conventional enteric microparticles. Colon targeting properties were evaluated

using coumarin-6 loaded nanospheres. The results indicated that prepared nanospheres showed

strongly pH dependent drug release properties in acidic and neutral pH values followed by

sustain release phase at pH 7.4. In–vivo studies using coumarin-6 loaded nanospheres displayed

higher colon levels and lower systemic availability of fluorescent marker when compared with

simple enteric coating. The nanosphere system combined the properties of pH- sensitivity,

control release and particulate targeting that was useful for colon specific delivery in

inflammatory bowel disease.

2.1.23. Wei et al., 2008 have studied colon specific pectin/ ethylcellulose film coated 5-

fluorouracil pellets in rats. The objective of study was to assess the bio-distribution and

pharmacokinetics of pectin/ ethylcellulose film-coated and uncoated pellets containing 5-

fluorouracil. Both coated and uncoated pellets were orally administered to the rats at a dosage

equivalent to 15 mg/kg. 5-FU concentrations in different parts of the gastrointestinal (GI) tract

and plasma were quantitatively analyzed using HPLC. The results suggested that 5-FU released

from uncoated pellets mainly distributed in the upper GI tract, however, 5-FU released from

coated pellets mainly distributed in the cecum and colon. In plasma, the observed mean Cmax

from the coated pellets group (3.65±2.3µg/mL) was lower than that of the uncoated pellets group

(23.54±2.9µg/mL). The AUC (area under curve) values obtained from the uncoated pellets and

the coated pellets were 49.08±3.1 and 9.06±1.2µgh/mL. The relatively high local drug

concentration with prolonged exposure time provided a potential to enhance anti-tumor efficacy

with low systemic toxicity for the treatment of colon cancer.

2.1.24. Pertuit et al., 2007 have worked on 5- amino salicyclic acid bound nanoparticles for the

therapy of inflammatory bowel disease. The objective of study was to design nanoparticles of 5-

ASA and reduce the side effect of 5-ASA in upper GIT. 5-ASA was covalently bound to

polycaprolactone. The nanoparticles were prepared by oil/water emulsification or

nanoprecipitation methods. Particle diameters were 200 nm and 350 nm for emulsification and



nanoprecipitation. Toxicity of the different formulations was evaluated on Caco-2 and HEK cell

culture. In-vitro drug release demonstrated significant drug retention inside the NP formulation.

Toxicity was slightly increased for 5-ASA grafted NP in comparison to blank NP. In-vivo,

clinical activity score and myeloperoxidase activity decreased after administration of all 5-ASA

containing formulations (untreated control: 28.0±5.6 U/mg; 5-ASA–NP (0.5 mg/kg): 15.2±5.6

U/mg; 5-ASA solution (30 mg/kg): 16.2±3.6 U/mg). Nanoparticle formulations allowed

lowering significantly the dose of 5-ASA. These oral nanoparticle formulations demonstrated

their therapeutic potential and appear to be a promising approach for the therapy of inflammatory

bowel disease.

2.1.25. Paharia et al., 2007 have developed Eudragit-coated pectin microspheres of 5-

fluorouracil for colon targeting. Pectin microspheres were prepared by emulsion dehydration

method. The yield of preparation and the encapsulation efficiencies were high for all pectin

microspheres. Eudragit-coating of pectin microspheres was performed by oil-in-oil solvent

evaporation method and evaluated for surface morphology, particle size and size distribution,

swellability, percentage drug entrapment, and in-vitro drug release in simulated gastrointestinal

fluids. The in-vitro drug release study of optimized formulation was also performed in simulated

colonic fluid in the presence of 2% rat caecal content. The release profile of fluorouracil from

Eudragit-coated pectin microspheres was pH dependent. In acidic medium, the release rate was

much slower and the drug was released quickly at pH 7.4. Eudragit-coated pectin microspheres

presented promising controlled release carriers for colon-targeted delivery of Fluorouracil.

2.1.26. Cai et al., 2003 have synthesized 5- aminosalicyclic acid and 5- acetyl aminosalicyclic

acid of polyanhydride- P (CBFAS). The main objective of work was to attain high local

concentration of 5- ASA in the colon site via oral administration. A novel polyanhydride,

poly[(5- carboxybutyl formamide)-2-acetyl salicylic anhydride] (P(CBFAS)), with 5-

aminosalicylic acid (5-ASA) incorporated into the polymer backbone was synthesized and

characterized by infrared, 1H-nuclear magnetic resonance, differential scanning calorimetry and

vapor pressure osmometry. The factors influencing the release profile of formulation was

examined. The results showed that the release rate of 5-ASA and 5-acetyl ASA increased with

increasing pH value and with decreasing molecular weights. In PBS (pH 8.0, 37 ̊C) total ASA

released was 8.0% for P (CBFAS) (Mn 10770) in 13 h, but only 1.1 and 2.6% at pH 2.0 and 6.5,

respectively. Enzymes including pepsin and trypsin, as well as rat gastric and jejunum contents



had little effect on the release rate of 5-ASA and 5-acetyl ASA at pH 2.0 and 6.5 (less than 4% in

13 h). However, the release rate of 5-ASA and 5-acetyl ASA was much fast in PBS (pH 8.0)

containing 5% of caecal contents, the total ASA released was 13.6% for the polymer in 13 h.

Study suggested that P (CBFAS) may be potentially useful in the colon specific delivery of 5-

ASA.

2.1.27. Wiwattanapatapee et al., 2003 have prepared dendrimeric conjugates for colonic

delivery of 5- aminosalicyclic acid. The objective of study was to design water soluble PAMAM

dendrimers conjugates for colonic delivery of 5-aminosalicyclic acid. The drug was bound to the

dendrimer using two different spacers containing azo-bond, p-aminobenzoic acid (PABA) and p-

aminohippuric acid (PAH). The results showed that PAMAM dendrimer conjugates containing

PABA and PAH spacers gradually released 5-ASA with time and the amount of drug released

was 45.6 and 57.0% of the dose in 24 h. The release of the drug from the commercial prodrug,

sulfasalazine was significantly faster than both conjugates. No 5-ASA was detected from the

incubation of dendrimer conjugates with the homogenate of the stomach or phosphate buffer at

pH 1.2 and 6.8. Only a small amount of 5-ASA was found after incubation of both conjugates

with the homogenate of the small intestine for 12 h. This indicated that the PAMAM dendrimer

can be used as a carrier for colon specific drug delivery.

2.1.28. Li et al., 2002 have evaluated in-vitro dissolution behavior for colon-specific drug

delivery system (CODES™) in multi-pH media using United States Pharmacopeia Apparatus II

and III. United States Pharmacopeia dissolution apparatus II (paddle) and III (reciprocating

cylinder) coupled with automatic sampling devices and software were used to develop a testing

procedure for acquiring release profiles of colon-specific drug delivery system (CODES™) drug

formulations in multi-pH media using acetaminophen as a model drug. Re-lease profiles in

artificial gastric fluid (pH 1.2), intestinal fluid (pH 6.8), and pH 5.0 buffer were determined. The

percent release of acetaminophen from coated core tablets was highly pH dependent. A release

profile exhibiting a negligible release in pH 1.2 and 6.8 buffers followed by a rapid release in pH

5.0 buffer was established. The release rate was reduced significantly with the increase in acid-

soluble Eudragit E coating levels, but lactulose loading showed only a negligible effect.

Apparatus III was demonstrated to be more convenient and efficient than apparatus II by

providing various programmable options in sampling times, agitation rates, and medium



changes, which suggested that the apparatus III approach has better potential for in-vitro

evaluation of colon-specific drug delivery systems.

2.1.29. Yano et al., 2002 have developed colon specific delivery of prednisolone appended α-

cyclodextrin conjugate. The aim of present work was to reduce the absorption of drug into upper

GIT track and also reduce systemic side- effect. In this, anti-inflammatory effect and systemic

side-effect of PD succinate/ α- cyclodextrin ester conjugation after oral administration was

studied using IBD model in rats. Anti-inflammatory effect of PD suc/ α-CyD conjugation was

compared with PD alone. The results indicated that PD suc/ α- CyD conjugate was useful as

delayed release type prodrug for colon specific delivery.

2.1.30. Krishnaiah et al., 2002 have investigated in-vitro drug release studies on guar gum-

based colon targeted oral drug delivery systems of 5- fluorouracil. The objective of study was to

develop novel tablet formulation for site- specific delivery of 5- fluorouracil to the colon without

release the drug in stomach and small intestine using guar gum as carrier. Fast disintegrating 5-

fluorouracil core table were coated with different ratio of guar gum. In-vitro drug release study

was carried out and amount of drug release was estimated by HPLC method. The result showed

that compression coated tablets containing 80% (FHV- 80) of guar gum provided maximum drug

release in the colon since they release only 2.38% of drug in the stomach and small intestine.

2.1.31. Tozaki et al., 2002 have designed chitosan capsules for colon specific drug delivery and

enhanced localization of 5- aminosalicyclic acid in the large intestine. The objective of this study

was to achieve the colon-specific delivery of an anti-ulcerative colitis drug using chitosan

capsules and to accelerate healing of 2,4,6-trinitrobenzene sulfonic acid sodium salt (TNBS)-

induced colitis in rats. In this, 5- Aminosalicylic acid (5-ASA) was used as a model of an anti-

inflammatory drug. The gastrointestinal transit of chitosan capsules was determined by counting

the number of capsules in the gastrointestinal lumen by celiotomy at certain times after their oral

administration to rats. The chitosan capsules reached the large intestine 3.5 h after oral

administration in rats. The release study of 5-ASA from chitosan capsule was carried out by

rotating basket method. The result showed that release of 5-ASA from the chitosan capsule

increased in the presence of rat caecal contents. After oral administration of chitosan capsules

containing 5-ASA, the concentrations of 5-ASA in the large intestinal mucosa were higher than

those in the CMC suspension. When 5-ASA was orally administered using chitosan capsules in

TNBS-induced colitis rats, showed better therapeutic effects with 5-ASA than with a 5-ASA



CMC suspension, as evaluated by the MPO activities, C/B ratio and the damage score. Therefore

chitosan capsules were useful carriers for the colon-specific delivery of anti-inflammatory drugs

including 5- ASA and the healing of TNBS-induced colitis in rats.

2.1.32. Krishnaiah et al., 2001 have prepared colon targeted drug delivery system for

mebendazole. The main objective of work was to develop colon targeted drug delivery system

for mebendazole using guar gum as carrier. The matrix tablets were prepared by wet granulation

method using different proportion of guar gum. The tablets were evaluated for content

uniformity and in-vitro drug release study of mebendazole from matrix tablets at different time

interval, which was estimated by HPLC method. The mebendazole matrix tablets containing

either 20% or 30% of guar gum showed no change either in physical appearance, drug content or

dissolution after storage at 45 ̊C/ 75% RH for three months.

2.2. Based on Curcumin delivery system

2.2.1. Ahmed et al., 2012 have studied the emulsion-based delivery systems for curcumin.

Curcumin has been reported to have many biological activities, but its application as a functional

ingredient is currently limited because of its poor water-solubility and bioaccessibility. This

study investigated the impact of different lipid-based formulations on curcumin encapsulation

and bioaccessibility. Oil-in-water nanoemulsion, were prepared with different lipids: long,

medium, and short chain triacylglycerols. An in-vitro model simulating small intestine digestion

conditions, characterized the rate and extent of lipid phase digestion. The bioaccessibility of

curcumin appeared to be slightly higher in conventional emulsions than in nanoemulsion.

2.2.2. Zhang Lin et al., 2012 have developed a novel folate-modified self-micro emulsifying

drug delivery system of curcumin for colon targeting. The objective of this study was to prepare,

characterize and evaluate a folate-modified self-micro emulsifying drug delivery system

(FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon,

facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells. The in-

vitro release results indicated that the obtained formulation of curcumin could reach the colon

efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence

microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind

with the folate receptors on the surface of positive folate receptors cell lines. In addition,



FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. FSMEDDS-filled

colon-targeted capsules may be a potential carrier for colon delivery of curcumin.

2.2.3. Kumar et al., 2012 have prepared mucoadhesive gels for treatment of oral sub mucous

fibrosis, which provide effect for extended period of time. Stress was given for improvised local

action of the drug with the addition of mucoadhesive polymer in the formulation. Curcumin was

taken as a model drug as it exhibits profound antitumor activity. The semisolid preparations

comprised of stabilizer like sodium meta-bisulphite, mucoretention / mucoadhesive polymers

like HEC, NaCMC and equal mixture of HEC & NaCMC, and were subjected for various

physicochemical parameters like pH, spreadability, drug content uniformity, extrudability, and

viscosity and I.R. studies. In-vitro drug release studies were carried out in phosphate buffer (pH

6.4). In vivo oral sub mucous fibrosis was induced in mice using marketed Gutkha preparation

and formulating into a mucoadhesive gel form and applying to mice oral mucosa for 6 months.

Histopathological observations reported that the study of mucoadhesive semi-solid drug design

for the treatment of oral sub mucous fibrosis can be useful for patients suffering from oral sub

mucous fibrosis.

2.2.4. Gandhy et al., 2012 determined the effects of curcumin and synthetic analogs on colon

cancer cell proliferation and apoptosis using standardized assays. The changes in Sp proteins and

Sp-regulated gene products were analyzed by western blots, and real time PCR was used to

determine microRNA-27a (miR-27a), miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA

expression.

2.2.5. Basnet et al., 2011 have performed clinical studies which suggested that cancer could be

prevented or reduced by treatment with anti-oxidant and anti-inflammatory drugs, therefore,

curcumin, a principal component of turmeric (a curry spice) showing strong anti-oxidant and

anti-inflammatory activities can prevent and treat cancer and other chronic diseases. However,

curcumin, a highly pleiotropic molecule with an excellent safety profile targeting multiple

diseases with strong evidence on the molecular level, could not achieve its optimum therapeutic

outcome in past clinical trials, largely due to its low solubility and poor bioavailability.

Curcumin can be developed as a therapeutic drug by improving delivery systems, enabling its

enhanced absorption and cellular uptake.

2.2.6. Vajpayee et al., 2011 have formulated and evaluated microspheres using natural polymers

for colon targeting. Curcumin is used to treat colon cancer, but it has very poor absorption in



upper GIT. As a part of drug delivery, colon offers near neutral pH, reduced digestive enzymatic

activity, a long transit time and increased responsiveness to absorption enhancers. Aim of study

was to identify suitable polymer based microspheres promising in-vitro mouth-to-colon release

profile. Curcumin loaded microspheres were prepared by ionic cross linking technique using

calcium chloride. Three formulations with each polymer using different concentrations were

formulated by ionic cross linking technique. In-vitro drug release study was performed using

simulated gastric fluid and simulated intestinal fluid for 8 hrs. Natural polysaccharides degraded

by the human colonic flora, have thus been investigated as colonic drug delivery carriers.

2.2.7. Upmanyu et al., 2011 have formulated, characterized and evaluated floating microspheres

of curcumin to achieve an extended retention in upper GIT, which resulted in enhanced

absorption and there by improved bioavailability. The microspheres were prepared by solvent

evaporation method using polymers such as hydroxyl propyl methyl cellulose (HPMC K 15 M),

ethyl cellulose in different ratios and curcumin in each formulation. In-vitro drug release was

performed by USP apparatus type I. The yield, particle size, Buoyancy percentage, drug

entrapment efficiency, and in-vitro drug release were studied.

2.2.8. Goindi et al., 2011 have developed Gastro-retentive floating beads of curcumin β-

cyclodextrin complex to treat stomach tumors by targeted and sustained release characteristics.

Aqueous solubility of curcumin was enhanced by complex formation with β-cyclodextrin. This

complex with enhanced solubility profile was further used to prepare multiple unit floating

beads. Floating beads of curcumin β-cyclodextrin complex were prepared by dripping a mixture

of sodium alginate and hydroxypropyl methylcellulose solution into calcium chloride solution

acidified with acetic acid. FBCC were evaluated for percent drug entrapment, diameter, surface

topography, buoyancy, in-vitro release and pharmacodynamic activity against forestomach

papillomas in albino female mice. The investigation revealed that floating beads possessed

optimum formulation characteristics. Results of in-vitro studies and anti-tumor studies in animals

suggested that FBCC can be safely and effectively used to treat neoplasia of stomach.

2.2.9. Wilken et al., 2011 have studied anticancer properties and therapeutic activity in head and

neck squamous cell carcinoma. Curcumin (bisferuloylmethane) is a polyphenol derived from the

Curcuma longa plant, commonly known as turmeric. More recently curcumin has been found to

possess anti-cancer activities via its effect on a variety of biological pathways involved in

mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and



metastasis. This study presents an overview of the current in-vitro and in vivo data supporting its

therapeutic activity in head and neck cancer as well as some of the challenges concerning its

development as an adjuvant chemotherapeutic agent.

2.2.10. Wichitnithad et al., 2011 had synthesized prodrug of curcuminoids for colon cancer

treatment. In this, succinyl derivatives of three curcuminoids were synthesized and anti-colon

cancer activity of the compound was evaluated using Caco-2 cells. Hydrolysis of prodrug in

phosphate buffer pH 7.4 and in human plasma followed pseudo 1st order kinetics. The result

suggested that succinate prodrugs of curcuminoid were stable in phosphate buffer and released

the parent curcumin derivatives readily in human plasma and showed anti-colon cancer activity.

2.2.11. Das et al., 2010 have encapsulated curcumin in alginate-chitosan-pluronic composite

nanoparticles for delivery to cancer cells. The composite nanoparticles were prepared by using

three biocompatible polymers alginate, chitosan, and pluronic by ionotropic pre-gelation

followed by polycationic cross-linking. Pluronic F127 was used to enhance the solubility of

curcumin in the Alginate-Chitosan nanoparticles. The in-vitro drug release profile along with

release kinetics and mechanism from the composite nanoparticles were studied under simulated

physiological conditions for different incubation periods. Cellular Internalization of curcumin-

loaded composite nanoparticles was confirmed from green fluorescence inside the HeLa cells.

The half-maximal inhibitory concentrations for free curcumin and encapsulated curcumin were

found to be 13.28 and 14.34 µm respectively.

2.2.12. Patel et al., 2009 have developed and characterized curcumin loaded transfersome for

transdermal delivery. Curcumin is widely used in potent anti-inflammatory herbal drug. Its

activity is similar to the NSAIDs in inflammatory pain management but main problem with

curcumin when given orally is its poor bioavailability due to less GI absorption. The

transfersomes were formulated by modified hand shaking method using surfactant such as

Tween 80 and Span 80 in various concentrations. Transfersome entrapped curcumin gel showed

better permeation as compared to plain drug gel.

2.2.13. Johnson et al., 2007 have focused on describing the pre-clinical and clinical evidence of

curcumin as a chemoprotective compound in colorectal cancer. The most practical approach to

reduce the morbidity and mortality of cancer is to delay the process of carcinogenesis through

the use of chemopreventive agents. This necessitates that safer compounds, especially those

derived from natural sources must be critically examined for chemoprevention. A spice common



to India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa.

Pre-clinical studies in a variety of cancer cell lines including breast, cervical, colon, gastric,

hepatic, leukemia, oral epithelial, ovarian, pancreatic, and prostate have consistently shown that

curcumin possessed anti-cancer activity in-vitro and in pre-clinical animal models. The robust

activity of curcumin in colorectal cancer has led to five phase I clinical trials being completed

showing the safety and tolerability of curcumin in colorectal cancer patients. In-vitro evidence

and clinical trials suggested that curcumin proved to be useful for the chemoprevention of colon

cancer in humans.

2.2.14. Cole et al., 2007 have studied neuro-protective actions of curcumin. Curcumin has an

outstanding safety profile and a number of pleiotropic actions with potential for neuroprotective

efficacy, including anti-inflammatory, antioxidant, and antiprotein-aggregate activities. Despite

concerns about poor oral bioavailability, curcumin has at least 10 known neuroprotective actions

and many of these might be realized in vivo. Indeed, accumulating cell culture and animal model

data showed that dietary curcumin is a strong candidate for use in the prevention or treatment of

major disabling age-related neurodegenerative diseases like Alzheimer’s, Parkinson’s, and

stroke.

2.3. Based on Flurbiprofen delivery system

2.3.1. Kawadkar et al., 2012 prepared genipin cross-linked chitosan microspheres of

flurbiprofen for intra-articular (i.a.) delivery. Emulsion-cross-linking method was used to prepare

the microspheres using different concentrations of genipin and drug-to-polymer ratios. The mean

particle size was found to be in the range of 5.18–9.74 µm with good % drug entrapment up to

80.97%. SEM indicated the spherical shape with smooth surface of drug-loaded cross-linked

microspheres. FTIR also indicated cross-linking of genipin with chitosan and the absence of

chemical interactions between drug, polymer, and cross-linker, which was further confirmed by

TGA. DSC and XRD revealed the molecular dispersion of drug within microspheres. The

optimized microspheres were able to release the drug for more than 10 h. The biocompatibility of

the microspheres in the rat (Sprague-Dawley) knee joints was confirmed by histopathology.

2.3.2. Mishra et al., 2011 designed a new formulation and evaluated of mucoadhesive buccal

film of flurbiprofen, which is designed for anti – inflammatory and analgesic therapy in the oral



cavity method. The film containing PVP and NaCMC was selected best promising film for the

delivery of the anti – inflammatory drug.

2.3.3. Deglon et al., 2011 developed an automated system for the on-line bioanalysis of dried

blood spots (on-line DBS). In this way, a prototype was designed for integration into a

conventional LC/MS/MS, allowing the successive extraction of 30 DBS toward the analytical

system without any sample pretreatment. The developed method was assessed for the DBS

analysis of flurbiprofen (FLB) and its metabolite 4- hydroxyflurbiprofen (OH-FLB) in human

whole blood (i.e. 5µL). The on-line DBS automated system was then successfully applied to a

pharmacokinetic study performed on healthy male volunteers after oral administration of a single

50-mg dose of FLB. Additionally, a comparison between finger capillary DBS and classic

venous plasma concentrations was investigated.

2.3.4. Veerappan et al., 2010 has formulated controlled release lipospheres of flurbiprofen by

using microencapsulation technology. By formulating sustained release lipospheres gastro

intestinal side effect were minimized. The formulation variables were studied with different

levels of butyl alcohol (co-surfactant), water and drug. In-vitro drug release profile study

revealed the formulations D1-D4 lipospheres showed sustained release.

2.3.5. Han et al., 2008 developed a method based on cloud-point extraction (CPE) for the

determination of flurbiprofen (FP) in rat plasma after oral and transdermal administration by

high-performance liquid chromatography coupled with UV detection (HPLC–UV). The non-

ionic surfactant Genapol X-080 was chosen as the extract solvent. Variables parameter affecting

the CPE efficiency were evaluated and optimized. Chromatography separation was performed on

a Diamond C18 column by isocratic elution with UV detection at 254 nm. The assay was linear

over the range of 0.2–50 and 0.1–10µg/ml for oral and transdermal administration, respectively,

and the lower limit of quantification (LLOQ) was 0.1µg/ml. After strict validation, the method

indicated good performance in terms of reproducibility, specificity, linearity, precision and

accuracy, and it was successfully applied to the pharmacokinetic study of flurbiprofen in rats

after oral and transdermal administration.

2.3.6. Mokhtar et al., 2008 developed Proniosomal gels or solutions of flurbiprofen based on

span 20, span 40, span 60 and span 80 without and with cholesterol. Nonionic surfactant vesicles

(niosomes) formed immediately upon hydrating proniosomal formulae. The entrapment

efficiency (EE%) of flurbiprofen (a poorly soluble drug) was either determined by exhaustive



dialysis of freshly prepared niosomes or centrifugation of freeze-thawed vesicles. The influence

of different processing and formulation variables such as surfactant chain length, cholesterol

content, drug concentration, total lipid concentration, negatively or positively charging lipids and

the pH of the dispersion medium on flurbiprofen EE% was demonstrated.

2.3.7. El-Kamel et al., 2008 have worked on oral colon targeted drug delivery systems for

treatment of inflammatory bowel disease. The aim of the study was to investigate prodrug of

NSAIDs as colon targeted delivery system for treatment bowel disease. For this purpose,

naproxen, sulindac and flurbiprofen were used. The carboxylic group of these drugs was

conjugated with amino group of L- aspartic acid or hydroxyl group of α- or β- cyclodextrin. In-

vitro and in-vivo study of prodrug was carried out. The results showed no significant hydrolysis

of prodrug in buffer having range pH 1.2- 7.2 over 72 h. Negligible % of drug release from Fbp-

α-CyD or Fbp-β-CyD prodrug was detected in rat stomach contents, intestine tissue and

intestinal contents homogenates. In rat colon homogenate, Fbp- α-CyD or Fbp-β-CyD released

60% of Fbp within 4 h. Oral administration of Fbp-β-CyD to rats after induction of colitis

significantly attenuated the severity of the colonic injury and reduced the score of the

macroscopic and microscopic damage. Additionally, there was a significant increase in the level

of GSH. The present study showed that Fbp-β-CyD prodrug was beneficial in treatment of

inflammatory bowel disease.

2.3.8. Xiu-Jin et al., 2008 developed stereoselective reversed-phase HPLC assay to determine

the enantiomers of flurbiprofen, ketoprofen and etodolac in human plasma. Chiral drug

enantiomers were extracted from human plasma with liquid–liquid extraction. Then flurbiprofen

and ketoprofen enantiomers reacted with the acylation reagent thionyl chloride and pre-column

chiral derivatization reagent (S)-(−)-α-(1-naphthyl)ethylamine (S-NEA), and etodolac

enantiomers reacted with S-NEA using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC)

and 1-hydroxybenzotriazole (HOBT) as coupling agents. The derivatized products were

separated on an Agilent Zorbax C18 (4.6mm×250 mm, 5µm) column with a mixture of

acetonitrile-0.01 mol·L−1

phosphate buffer (pH 4.5) (70:30, v/v) for flurbiprofen enantiomers,

acetonitrile-0.01 mol·L−1

phosphate buffer (pH 4.5) (60:40, v/v) for ketoprofen enantiomers and

methonal-0.01 mol·L−1

potassium dihydrogen phosphate buffer (pH 4.5) (88:12, v/v) for

etodolac enantiomers as mobile phase.



2.3.9. Orlu et al., 2006 have designed and evaluated colon specific drug delivery system

containing flurbiprofen microsponges. Microsponges containing flurbiprofen and Eudragit

RS100 were prepared by Quassi-emulsion solvent diffusion method. Flurbiprofen was entrapped

into a commercial Microsponge 5640 system using entrapment method. The thermal behavior,

surface morphology, particle size and pore structure of microsponges were examined. The colon

specific formulations were prepared by compression coating and also pore plugging of

microsponges with pectin: hydroxypropylmethyl cellulose (HPMC) mixture followed by

tableting. In-vitro dissolution studies were done on all formulations and the results were

kinetically and statistically evaluated. The pore shapes of microsponges prepared by quasi-

emulsion solvent diffusion method and entrapment method were found as spherical and

cylindrical holes, respectively.



2.4. DRUG REVIEW

2.4.1. CURCUMIN

Curcumin ‘yellow-colored’ Indian spice is used worldwide for health care, prevention and

treatment of various diseases as well as preservation of food and coloring agent. It is a naturally

occurring bioactive phytochemical which is considered most successful in modern medicine. It is

used worldwide as spice, food additive or dietary pigment. Chemically, it is a polyphenol and

potent curcuminoid which is responsible for imparting yellow color. It is mainly derived from

rhizomes of plant Curcuma longa, family Zingiberaceae (Jurenka et al., 2009, Huang et al.,

2011). Turmeric consists of three curcuminoids i.e., curcumin, desmethoxycurcumin and bis-

desmethoxycurcumin. Other chemical constituents present are zingiberene, curcumenol,

curcuma, eugenol, tetrahydrocurcumin, triethylcurcumin, turmerin, turmerones, and turmeronols.

These natural phenols are responsible for the yellow colour of turmeric (Anand et al., 2003,

Aggarwal et al., 2007). Curcumin was first isolated in 1815 by Vogel and its chemical structure

(Fig. 2.1) was determined by Roughley and Whiting in 1973 (Chattopadhyay et al., 2004). Table

2.1 shows the profile of Curcumin.

2.4.1.1. Structure of curcumin

OCH3

OH

O OH

H3CO

HO

Fig. 2.1: Molecular structure of curcumin



Table 2.1: Profile of Curcumin

IUPAC name 1, 7-Bis (4-hydroxy-3-methoxyphenyl)-1, 6-

heptadiene-3, 5-Dione

Molecular Formula C21H20O6

Molecular Weight 368.38 g/mol

Melting Point 179-183ᵒC

Appearance Bright yellow powder

Solubility Slightly soluble in water, poorly soluble in acidic

pH, highly soluble in alkaline pH and in organic

solvents.

Storage It is stored in ambered colored bottles.

Lethal dose 12.5 g/day

Half life 0-48 h

Uses Anti-inflammatory, anti-carcinogenic, anti-

microbial, analgesic, anti-diabetic,

neuroprotective, anti-fungal, anti-protozoan,

cardioprotective.

2.4.1.2. Role of Curcumin in diseases

Curcumin helps in maintenance of health and prevention of diseases. It has been widely used for

centuries in Ayurveda and Traditional Chinese Medicine to cure biliary disorders, anorexia,

diabetic wounds, cough, hepatic disorders and sinusitis (Cine et al., 2013). Curcumin is very safe,

non-toxic even at higher doses and pleiotropic molecule which acts on many different target

molecules like growth factors and their receptors, cytokines and enzymes (Jurenka et al., 2009,

Das et al., 2010). It has a wide range of pharmacological effects against various diseases like

cancer by suppressing the proliferation of tumor cells of lung cancer, breast cancer, colon cancer,

skin cancer, oral sub-mucosal cancer and many other diseases like anti-inflammatory, diabetes,

allergies, arthritis, Alzheimer’s disease, Crohn’s disease, cardiovascular disease, skin diseases,

anti-microbial, anti-angiogenic, osteoporosis, psoriasis and suppresses thrombosis and

myocardial infarction also (Aggarwal et al., 2007, Jurenka et al., 2009 and Shishodia et al.,

2005). Curcumin prevents oxidation of low density lipoprotein which helps in reducing blood



cholesterol level (Huang et al., 2011). Curcumin is non-toxic and have decreased side-effects

without any loss to its therapeutic efficacy. Along with the pharmacological actions of curcumin,

it also has the photo stabilizing property to protect photo-labile drugs present in solutions, topical

formulations and soft gelatin capsules (Zandi et al., 2010). Curcumin is used in various health

supplements too. Clinically, curcumin has already been used to reduce post-operative

inflammation. Safety evaluation studies indicate that both turmeric and curcumin are well

tolerated at a very high dose without any toxic effects.

2.4.1.3. Mechanism of action of Curcumin on Inflammatory Bowel Disease [IBD]

IBD- Crohn’s disease and Ulcerative colitis

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the mucosal

membrane of the small and/or large intestine. Although many treatments have been

recommended for IBD, they do not treat the cause but are effective only in reducing the

inflammation and accompanying symptoms in up to 80% of patients (Philip et al., 2009).

Curcumin is a highly pleiotropic molecule capable of interacting with numerous molecular

targets involved in inflammation. Curcumin modulates the inflammatory response by down-

regulating the activity of cyclooxygenase-2 (COX-2), lipoxygenase, and inducible nitric oxide

synthase (iNOS) enzymes; inhibits the production of the inflammatory cytokines tumor necrosis

factor-alpha (TNF-a), interleukins (Chattopadhyay et al., 2004). Curcumin acts via inhibiting

COX-2 and iNOS by suppressing necrotic factor kappa B (NF-κB) activation. NF-κB, a

ubiquitous eukaryotic transcription factor, is involved in regulation of inflammation, cellular

proliferation, transformation, and tumorigenesis. Curcumin suppresses NF-κB activation and

proinflammatory gene expression by blocking phosphorylation of inhibitory factor I-kappa B

kinase (IκB). Suppression of NF-κB activation subsequently down-regulates COX-2 and iNOS

expression, inhibiting the inflammatory process and tumorigenesis (Chattopadhyay et al., 2004,

Jobin et al., 1999 and Surh et al., 2001).



2.4.2. FLURBIPROFEN

Flurbiprofen, a propionic acid derivative, is a nonsteroidal anti-inflammatory drug (NSAID) with

antipyretic and analgesic activity (Han et al., 2008). Oral formulations of flurbiprofen may be

used for the symptomatic treatment of rheumatoid arthritis, osteoarthritis and other inflammatory

conditions. Flurbiprofen may also be used topically prior to ocular surgery to prevent or reduce

intraoperative miosis. Flurbiprofen is structurally and pharmacologically related to fenoprofen,

ibuprofen, and ketoprofen (Fig. 2.2). Table 2.2 shows the profile of Flurbiprofen.

Category:

• Anti-inflammatory Agent

• Cyclooxygenase Inhibitors

• Analgesics

• Analgesics, Non-Narcotic

• Antipyretics

• Non-steroidal Anti-inflammatory Drugs (NSAIDs)

2.4.2.1. Structure of Flurbiprofen

OH

F

O

Fig. 2.2: Molecular structure of Flurbiprofen



Table 2.2: Profile of Flurbiprofen

IUPAC name 2-(3-fluoro-4-phenylphenyl) propanoic acid

Molecular Formula C15H13FO2

Molecular Weight 244.2609g/mol

Melting Point 114-117ᵒC

Appearance White to slightly yellow crystalline powder

Solubility Slightly soluble in water, soluble in organic

solvents.

Storage Stored at room temperature

Half life 4.7-5.7 h

pka value 4.22

Log P 4.24

Uses Anti-inflammatory, anti-pyretic, analgesic.

2.4.2.2. Mechanism of Action: The anti-inflammatory effect of flurbiprofen occurs via

reversible inhibition of cyclooxygenase (COX), the enzyme responsible for the conversion of

arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2) in the

prostaglandin synthesis pathway (Kawadkar et al., 2012). This effectively decreases the

concentration of prostaglandins involved in inflammation, pain, swelling and fever. Flurbiprofen

is a non-selective COX inhibitor and inhibits the activity of both COX-1 and COX -2.

2.4.2.3. Pharmacokinetics

Absorption: Flurbiprofen is rapidly and almost completely absorbed following oral

administration. Peak plasma concentrations are reached 0.5 - 4 hours after oral administration

(Yan-Mei et al., 2009).

Distribution: Distribution into human body tissues and fluids not fully characterized. Distribute

into milk very small amount.

Plasma Protein Binding: >99% (principally albumin).

Metabolism: Extensively metabolized. CYP2C9 plays an important role in the metabolism of

flurbiprofen to its major metabolite, 4′-hydroxyflurbiprofen, which has weak anti-inflammatory

activity.



Excretion: Following oral dosing, approximately 70% of the flurbiprofen dose is eliminated in

urine as parent drug and metabolites, with <3% excreted as unchanged drug.

2.5. EXCIPIENTS REVIEW

2.5.1. Chitosan: Chitosan is a linear polysaccharide, composed of glucosamine and N-

acetylglucosamine, produced by partial deacetylation of chitin by alkaline or enzymatic

hydrolysis (Shaji et al., 2010). Chitin is the major component of the exoskeleton of crustaceans,

insects, cell wall of fungi and yeast. For the commercial production, chitin from shells of prawns,

crabs, or other crustacean is used. Chitosan is a polysaccharide (Fig. 2.3) obtained by N-

deacetylation from chitin and it has been widely investigated as a carrier for novel delivery

systems owing to its biodegradability, biocompatibility and safety. Chitosan (low mol. wt.,

viscosity 20-200 cP) is prone to degradation by the colonic microflora and therefore it can be

used for colon specific drug delivery incorporated in pH sensitive polymer (Rabiskova et al.,

2012). Table 2.3 shows the profile of chitosan.

2.5.1.1. Structure of Chitosan

O

O

O

O

O

CH2OH

OHOH

HN

OH

HN

CH2OH

OH

HN

OH

CH2OH

CH3 CH3 CH3

O O O

n

Fig. 2.3: Molecular structure of Chitosan



Table 2.3: Profile of Chitosan

Synonyms 2-Amino-2-deoxy-(1,4)-β-D-glucopyranan; deacetylated chitin;

deacetylchitin; β-1,4-poly-D-glucosamine; poly-D-glucosamine;

poly-(1,4-β-D-glucopyranosamine).

Molecular weight 10 000–1 000 000 Daltons

Functional category Coating agent; disintegrant; film-forming agent; mucoadhesive;

tablet binder; viscosity-increasing agent.

Applications Chitosan is used in cosmetics and is under investigation for use in

a number of pharmaceutical formulations. The suitability and

performance of chitosan as a component of pharmaceutical

formulations for drug delivery applications has been investigated

in numerous studies. These include controlled drug delivery

applications, use as a component of mucoadhesive dosage forms,

rapid release dosage forms, improved peptide delivery, colonic

drug delivery systems and use for gene delivery. Chitosan has

been processed into several pharmaceutical forms including gels,

films, beads, microspheres, tablets and coatings for liposomes.

Solubility Sparingly soluble in water; practically insoluble in ethanol (95%),

other organic solvents, and neutral or alkali solutions at pH above

approximately 6.5.

Storage and Stability Chitosan powder is a stable material at room temperature,

although it is hygroscopic after drying. Chitosan should be stored

in a tightly closed container in a cool, dry place. The PhEur 2005

specifies that chitosan should be stored at a temperature of 2–8°C.

2.5.2. Eudragit S 100 [Polymethacrylates]: Eudragit is anionic copolymer based on

methacrylic acid and methacrylate (Fig. 2.4). It is a pH sensitive polymer mainly used for colon

targeting (Pandey et al., 2012). Polymethacrylates are primarily used in oral capsule and tablet

formulations as film-coating agents. Depending on the type of polymer used, films of different

solubility characteristics can be produced. Eudragit E is used as a plain or insulating film former;

it is soluble in gastric fluid below pH 5. Eudragit L, S and FS types are used as enteric coating

agents because they are resistant to gastric fluid. Different types are available that are soluble at

different pH values: e.g. Eudragit L is soluble at pH > 6; Eudragit S and FS are soluble at pH >

7. Table 2.4 shows the profile of Eudragit S 100.



2.5.2.1. Structure of Eudragit S 100

C CO

OH

O

OCH3

Fig. 2.4: Molecular structure of Eudragit S 100

Table 2.4: Profile of Eudragit S 100

Physical properties It is a solid substance in form of a white powder with a faint

characteristic odour.

Empirical formula (C5O2H8)n

Functional category Film former; tablet binder; tablet diluent.

Targeted drug release area Colon delivery

Dissolution At/above pH 7

Characteristics Granulation of drug substances in powder form for controlled

release, effective and stable enteric coatings with a fast dissolution

in the upper Bowel, site specific drug delivery in intestine and

variable release profiles.

Chemical name Poly(methacrylic acid-methyl methacrylate) 1:2

Appearance Clear, rigid.

Acrylic resistance Excellent resistance (no attack) to Mineral Oils

Good resistance (minor attack) to Dilute Acids, Aldehydes and

Aliphatic Hydrocarbons. Limited resistance (moderate attack and

suitable for short term use only) to Bases. Poor resistance (not

recommended for use) with Concentrated Acids, Alcohols, Esters,

Aromatic and Halogenated Hydrocarbons, Ketones, Vegetable Oils

and Oxidizing Agents.

Properties (a) It can deliver the active drug directly at the site of action. (c) It

possesses possible fewer side effects.

Advantages of protective

Eudragit coating:

pH dependent drug release, protection of sensitive actives, masking

of taste and odour, moisture protection and improved passage of

dosage form. Time-controlled drug release therapeutically

customized release profiles and reduces the dosage.



2.5.3. Ethanol: Used as an organic solvent for drug and polymers (Fig. 2.5) (Merck Index,

2006). Table 2.5 shows the profile of ethanol.

2.5.3.1. Structure of Ethanol

OH

Fig. 2.5: Molecular structure of Ethanol

Table 2.5: Profile of Ethanol

Synonyms Ethyl alcohol, ethyl hydroxide, grain alcohol, methyl carbinol.

Empirical formula C2H5OH

Molecular weight 46.07g/mol

Functional category Anti-microbial preservative [10% v/v], disinfectant [90% v/v],

skin penetrant, solvent [up to 85% v/v].

Applications Ethanol and aqueous ethanol solutions of various concentrations

are widely used in pharmaceutical formulations and cosmetics;.

Although ethanol is primarily used as a solvent, it is also

employed in solutions as an antimicrobial preservative. Topical

ethanol solutions are also used as penetration enhancers and as

disinfectants [Karabit et. al., 1989, Liu et. al., 1991 and Chiori et.

al., 1983].

Uses Solvent in film coating, solvent in injectable solutions, solvent in

oral liquids at variable concentrations (%v/v) and as solvent in

topical products 60-90% v/v.

Boiling Point 78.15◦C

Flammability Readily flammable, burns with blue and smokeless flame.

Solubility Miscible with chloroform, ether, glycerin, and water.

Storage and Stability Aqueous ethanol solutions may be sterilized by autoclaving or by

filtration and should be stored in airtight containers, in a cool

place.

2.5.4. SPAN 80: Sorbitan monoesters are a series of mixtures of partial esters of sorbitol and its

mono- and dianhydrides with fatty acids (Fig. 2.6). Sorbitan diesters are a series of mixtures of

partial esters of sorbitol and its monoanhydride with fatty acids. Sorbitan esters are widely used



in cosmetics, food products, and pharmaceutical formulations as lipophilic nonionic surfactants.

They are mainly used in pharmaceutical formulations as emulsifying agents in the preparation of

creams, emulsions, and ointments for topical application. When used alone, sorbitan esters

produce stable water-in-oil emulsions and microemulsions but are frequently used in

combination with varying proportions of a polysorbate to produce water-in-oil or oil-in-water

emulsions or creams of varying consistencies (Merck Index, 2006). Table 2.6 shows the profile

of span 80.

2.5.4.1. Structure of SPAN 80

O

O

OH

OH

O

OH

Fig. 2.6: Molecular structure of SPAN 80

Table 2.6: Profile of SPAN 80

Synonyms Sorbitan monooleate, ionets 80, montan 80, glycomulo, sorgen 80

Empirical Formula C24H44O6

Molecular weight 428g/mol

Appearance Liquid, clear, viscous, yellow coloured

Stability Stable and combustible.

Functional Category Emulsifying agent, nonionic surfactant, solubilizing agent,

wetting and dispersing/suspending agent.

Solubility Generally soluble or dispersible in oils, they are also soluble in

most organic solvents. In water, although insoluble, they are

generally dispersible.

Applications Used in cosmetics, food products, and pharmaceutical

formulations as lipophilic nonionic surfactants.



2.5.5. Acetone: Used as an organic solvent for drug and polymers (Fig. 2.7). It is also present as

an excipient in some pharmaceutical drugs (Merck Index, 2006). Table 2.7 shows the profile of

acetone.

2.5.5.1. Structure of Acetone

C

C C

HH

H H

HH

O

Fig. 2.7: Molecular structure of Acetone

Table 2.7: Profile of Acetone

Synonyms Dimethylformaldehyde; dimethyl ketone; propane 2-one.

Empirical Formula C3H6O

Molecular Weight 58.08g/mol

Description Acetone is a colorless volatile, flammable, transparent

liquid, with a sweetish odor and pungent sweetish taste.

Boiling Point 56.2ᵒ C

Melting Point 94.3ᵒ C

Solubility Soluble in water, freely soluble in ethanol

Stability and Storage Acetone should be stored in a cool, dry, well-ventilated

place out of direct sunlight.

2.5.6. Acetic acid: Concentrated acetic acid (Fig. 2.8) is corrosive to skin and must therefore be

handled with appropriate care, since it can cause skin burns, permanent eye damage and irritation

to the mucous membranes (Merck Index, 2006). Table 2.8 shows the profile of acetic acid.

2.5.6.1. Structure of Acetic acid

CH3C

O

OH

Fig. 2.8: Molecular structure of Acetic acid



Table 2.8: Profile of Acetic acid

Nonproprietary Names BP: Glacial acetic acid, JP: Glacial acetic acid,

USP: Glacial acetic acid

Synonyms Ethanoic acid, Vinegar acid

Empirical formula and Molecular

weight

C2H4O2, 60.05

Functional category Acidifying agent

Description It occurs as a crystalline mass or a clear, colorless

volatile solution with a pungent odor.

Solubility Miscible with ethanol, ether, glycerin, water, and

other fixed and volatile oils.

Stability and Storage conditions Stored in an airtight container in a cool, dry place.

Boiling and Melting point 118°C (b. p.), 17°C (m. p.)

2.5.6. Carboxy methyl cellulose (CMC): Carboxymethylcellulose is widely used in oral and

topical pharmaceutical formulations, primarily for its viscosity-increasing properties (Fig. 2.9).

Viscous aqueous solutions are used to suspend powders intended for either topical application or

oral and parenteral administration. Carboxymethylcellulose sodium may also be used as a tablet

binder and disintegrant and to stabilize emulsions (Merck Index, 2006). Table 2.9 shows the

profile of carboxy methyl cellulose.

2.5.6.1. Structure of Carboxy methyl cellulose

O

OH

OH

CH2OCH2COOH

O

O

O

CH2OCH2COOH

OH

Fig. 2.9: Molecular structure of Carboxy methyl cellulose



Table 2.9: Profile of Carboxy methyl cellulose

Nonproprietary Names BP: Carmellose Sodium, JP: Carmellose Sodium,

USP: Carboxy MethylCellulose

Synonyms cellulose gum; CMC

Empirical Formula and Mol. wt. [C6H7O2(OH)x(OCH2COOH)y]n 90 000–700 000

Functional Category Suspending agent, viscosity-increasing agent and

water-absorbing agent.

Description It occurs as a white to almost white, odorless, granular

powder.

Solubility Practically insoluble in acetone, ethanol (95%), ether

and toluene.

Stability and Storage Conditions

Aqueous solutions stored for prolonged periods should

contain an antimicrobial preservative.

The bulk material should be stored in a well-closed

container in a cool and dry place.

Melting point Browns at approximately 227°C, and chars at

approximately 252°C.

Uses Emulsifying agent, Gel forming agent.

2.5.7. Liquid Paraffin: It is used primarily as an excipient in topical pharmaceutical

formulations where its emollient properties are exploited in ointment bases (Fig. 2.10). It is also

used in ophthalmic formulations. Light mineral oil is additionally used in oil-in-water and

polyethylene glycol/glycerol emulsions, as a solvent and lubricant in capsules and tablets, as a

solvent and penetration enhancer in transdermal preparations and as the oily medium used in the

microencapsulation of many drugs (Merck Index, 2006). Table 2.10 shows the profile of liquid

paraffin.

2.5.7.1. Structure of Liquid Paraffin

CnH2n 2

Fig. 2.10: Molecular structure of Liquid Paraffin



Table 2.10: Profile of Liquid Paraffin

Nonproprietary Names BP: Light liquid paraffin

JP: Light liquid paraffin

USPNF: Light mineral oil

Synonyms Light white mineral oil, light liquid petrolatum.

Empirical Formula and Molecular

Weight

Light mineral oil is a mixture of refined liquid saturated

hydrocarbons obtained from petroleum. It is less viscous

and has a lower specific gravity than mineral oil.

Functional Category Emollient, lubricant.

Description Light mineral oil is a transparent, colorless, viscous oily

liquid without fluorescence in daylight.

Solubility

Soluble in chloroform, ether, and hydrocarbons;

sparingly soluble in ethanol (95%); practically insoluble

in water.

Storage Conditions Light mineral oil should be stored in an airtight container

in a cool, dry place and protected from light.

Boiling point >360°C

Uses Ophthalmic ointments, Otic preparations, Topical

emulsions.

2.5.8. Zinc Chloride: ZnCl2 is hygroscopic and even deliquescent (Fig. 2.11). Samples should

therefore be protected from sources of moisture including the water vapor present in ambient air.

Zinc chloride finds wide application in textile processing, metallurgical fluxes and chemical

synthesis (Merck Index, 2006). Table 2.11 shows the profile of zinc chloride.

2.5.8.1. Structure of Zinc Chloride

Zn

ClCl

Fig. 2.11: Molecular structure of Zinc Chloride



Table 2.11: Profile of Zinc Chloride

Synonyms Zinc dichloride fume.

Empirical Formula and Molecular Weight ZnCl2, 136.3

Description Zinc chloride is a white crystalline solid.

Solubility Acetone: slightly soluble and water solubility

435% at 70° F.

Stability and Storage Conditions Zinc chloride can be stored in properly closed

containers under cold to warm environment, in

a temperature range of 2 to 40 degree Celsius.

Boiling point and Melting point 1350°F (b.p.), 293°C (m.p.)

Uses It is used for preserving wood, in soldering

fluxes, as a catalyst in chemical metals.

Documents

10. Review of Literature - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/19935/1/10. review of literature.pdf2. REVIEW OF LITERATURE 2.1. Based on colon specific drug delivery