REVIEW OF LITERATURE:

Indrajeet Gonjari1 et al., (2009) studied the potential of various

mucoadhesive polymers on the retain ability of the ophthalmic gel of fluconazole in

the intraocular therapy. Ocular delivery of topically applied drugs such as fluconazole

is hampered by elimination of the solution due to tear turnover, so an in situ gelling

thermoreversible mucoadhesive gel was formulated. Thermosensivity mucoadhesive

gels were prepared using the cold method along with poloxamer 407 and different

mucoadhesive polymers such as hydroxy ethyl cellulose (HEC), hydroxy propyl

methyl cellulose (HPMC) K4M, and polyvinyl pyrrolidone (PVP) K30.

Harish Nairy Matapady et al., (2009) designed an in situ gel formulation of

fluconazole with mucoadhesive properties for prolonging buccal residence time and

thereby better therapeutic effects. In addition, they afford intimate contact between a

dosage form and the absorbing tissue, which may result in high drug concentration in

local area. The in situ formulation will have better patient acceptability since the

formulation will be applied in the form of sols, which upon contact will form the

corresponding gels causing less irritation or pain.

Joseph Jagur Grodzinskia., (2010) proposed that hydrogel system are

formed when a three-dimensional polymeric network is loosely crosslinked. They are

swollen by water but not dissolved in it. Hydrogels may display reversible sol–gel

transitions, induced by changes in the environmental conditions such as temperature,

pH, ionic strength, phase separation, wave length of light, crystallinity, etc. Hydrogel

is described as smart, when sharp transition is induced by small change in such

conditions. For the shape memory hydrogels,soln-gel reversible change in shape may

also be induced by such stimuli like ion,pH,temperature reverse.

Basavaraj Nanjawade et al., (2007) made an attempt of ophthalmic drug

delivery for sustaining the drug delivery in the ocular cavity using in situ hydrogels.

The conventional ophthalmic drug delivery systems like solutions, suspensions, and

ointments show drawbacks such as increased precorneal elimination, high variability

inefficiency, and blurred vision respectively. In situ-forming hydrogels are liquid

before administration and undergo phase transition in the ocular cul-de-sac to form

viscoelastic gel depot and this provides a response to environmental changes. In the

past few years, an impressive number of novel temperature induced, pH sensitive, and

ion induced in situ-forming systems have been reported for sustain ophthalmic drug

delivery.

Sudipta Ganguly et al., (2004) investigated a novel chitosan-glyceryl

monooleate (GMO) in situ gel system for sustained drug delivery and targeting. The

delivery system consisted of 3% (w/v) chitosan and 3% (w/v) GMO in 0.33 M citric

acid. In situ gel was formed at a biological pH. In vitro release studies were

performed in Sorensen‘s phosphate buffer (pH 7.4).

Wataru Kubo et al., (2003) has studied the effect of gellan gum (1.0% w/v)

and sodium alginate (1.5% w/v) containing ca++

ions in a complexed form on the

sustainability of para amino phenol delivery by the formation of hydrogels in the

stomach of rabbit and rat after oral administration. It resulted in the formation of in

situ gel depots in rabbit and rat stomachs as a consequence of the release of the

calcium ions in the acidic environment. In vitro studies demonstrated diffusion-

controlled release of para amino phenol from the gels over a period of 6h.

Yuthika Samaranayake et al., (2001) reviewed the current status of animal

models for evaluating anti fungal activity. The monkey, rat, and mouse are the

selection models for investigating oral candidiasis, but comparisons between the same

or different models appear difficult, because of variables such as the study design, the

number of animals used, their diet, the differences in Candida strains, and the duration

of the studies. These variables despite, gives, (I) the monkeys primate model is ideal

for investigating Candida-associated denture stomatitis since both erythematous

and

pseudo membranous lesions have been produced in with prosthetic plates; they are,

however, expensive and difficult to obtain and maintain. (ii) The rat animal model

(both Sprague-Dawley and Wistar) is well proven for observing chronic oral Candida

colonization and infection, due to the ease of breeding and handling and their ready

availability. (iii) Mice are comparable, but in addition there are well characterized

variants simulating immunologic and genetic abnormalities (e.g., athymic, euthymic,

murine-acquired

immunodeficiency syndrome, and severe combined immuno-

deficient models.

Yasuki kamai et al., (2001) studied the murine model of oropharyngeal

candidiasis. Mice were immune suppressed with cortisone acetate, anesthetized, and

then inoculated by placing cotton wool balls saturated with Candida albicans

sublingually for 2 h. A prolonged, reproducible infection was induced. This model

may be useful for antifungal pathogenesis studies.

Thomas Walsh et al., (2000) investigated the oropharyngeal and esophageal

candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised

patients. A group of azole-resistant oropharyngeal and esophageal candidiasis is a

refractory form of this infection occurring particularly in human immunodeficiency

virus (HIV)-infected patients. They reported the potential correlation between in vitro

susceptibility to fluconazole and in vivo response in a rabbit model of fluconazole-

resistant oropharyngeal and esophageal candidiasis. MICs of fluconazole were

determined by NCCLS methods. Three fluconazole-susceptible (FS) (MIC, <0.125

mg/ml) and three fluconazole-resistant (FR) (MIC, >64 mg/ml) isolates of Candida

albicans from prospectively monitored HIV-infected children with oropharyngeal and

esophageal candidiasis were studied.

Sudhakar et al., (2006) reviewed the current status of rapid developments in

the field of molecular biology and gene technology resulted in generation of many

macromolecular drugs including peptides, proteins, polysaccharides and nucleic acids

in great number possessing superior pharmacological efficacy with site specificity and

devoid of untoward and toxic effects. Over the last few decades' pharmaceutical

scientists all over the world are trying to explore transdermal and transmucosal routes

as an alternative to injections. between the various transmucosal sites available, mucosa

of the buccal cavity was found to be the most convenient and easily accessible site for

the delivery of therapeutic agents for both local and systemic delivery as retentive

dosage forms, because it has expanse of smooth muscle which is relatively immobile,

abundant vascularization, rapid recovery time after exposure to stress and the near

absence of langerhans cells. Direct entry to the systemic circulation through the

internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to

high bioavailability. Additionally, these dosage forms are self-administrable, cheap and

have superior patient compliance.

According to Salamat-Miller et al., (2005) the buccal delivery of the desired

drug using mucoadhesive polymers has been the subject of interest since the early

1980s. Starting with a review of the oral mucous membrane, mechanism of drug

permeation, and characteristics of the desired polymers, this article then proceeds to

cover the theories behind the adhesion of bioadhesive polymers to the mucosal

epithelium. Further, we focus on the new generation of mucoadhesive polymers such

as thiolated polymers, followed by the recent mucoadhesive formulations for buccal

drug delivery.

In the view of Enel et al., (2000) Topical delivery of antimicrobial agents is

the most broadly accepted approach aimed at prolonging active drug concentrations in

the oral cavity. As most anti fungal do not posses inherent ability to bind to the oral

mucosa, this is best achieved through improved formulations. Chitosan, a partially

deacetylated chitin, Chitosan is a biologically safe biopolymer, prolongs the adhesion

time of oral gels and drug release from them. Chitosan also inhibits the mucoadhesion

of Candida albican to human buccal cells and has antifungal activity. The antifungal

agent, chlorhexidine gluconate, also decreases C. albicans adhesion to oral mucosal

cells. Drug diffusion of Chx from gels was maintained for 3 h.

By Miyazaki et al., (2001) three liquid preparations with in situ gelling

properties have been assessed for their potential for the oral delivery of cimetidine.

The preparations were dilute solutions of: (a) enzyme-degraded xyloglucan, which

form thermally reversible gels on warming to body temperature; (b) gellan gum and;

(c) sodium alginate both containing complexed calcium ions that form gels when

these ions are released in the acidic environment of the stomach. The in vitro release

of cimetidine from gel system of each of the compounds followed root-time kinetics

over a period of 6h.

David Jones et al., (2009) described the formulation and characterization of

the viscoelastic, mechanical and mucoadhesive properties of thermo responsive,

binary polymeric systems composed of poloxamer (P407) and poly(acrylic acid, C

974P that were designed for use as a drug delivery platform within the oral cavity.

The formulations were prepared containing 10, 15 and 20% (w/w) poloxamer (407)

and 0.10–0.25% (w/w) poly (acrylic acid, 934P). Binary systems composed of 10%

(w/w) P407 and C934P were elastoviscous, were easily deformed under stress and did

not exhibit mucoadhesion, formulations composed of 20% (w/w) P407 and C934P

exhibited pronounced mucoadhesive properties.

According to Shivanand Swamy et al., (2008) a major problem in ophthalmic

therapeutics is the attainment of optimal drug concentration at the site of action, the

effective dose administered may be altered by increasing the retention time of

medication into the eye by using in situ gel forming systems. The system is to prepare

and evaluate novel in situ gum based ophthalmic drug delivery system of linezolid. In

this system Hydroxypropyl guar (HPG) and xanthum (XG) were used as gum with the

combination of hydroxyethyl cellulose (HEC), carbopol (CP), and sodium alginate as

viscosity enhancing agents. While, Gynozol gave the lowest percentage of the

cured cases (70%) sited sustained release of drug from formulation over a period of

6hr thus increasing residence time of the drug. A novel in situ gelling system

containing gums may be a valuable substitute to the conventional systems.

Shi-lei Cao et al., (2009) described the preparation of a novel in situ gel system for

nasal delivery of MF and study its efficacy on allergic rhinitis model. An ion-activated in

situ gel was developed and characterized with gelrite as a carrier. The system was stable

kept at 40 ± 2 ° C for 6 months. MF in gelrite produced obviously effect on allergic rhinitis

at the doses of 20 (g/body) following intranasal administration, and the efficacy was

significantly superior to that of the common suspension (P< 0.01). An ion induced MF in

situ gel system is a promising approach for the intranasal delivery of MF for the

therapeutic effects improvement.

Afaf et al., (2008) gave an account on Miconazole nitrate buffered gels in the

treatment of the protozoal and anaerobic bacterial infection of the vagina. Miconazole

was formulated into buffered gels (pH 4.75) using different hydrophilic gel bases,

including hydroxy propyl methyl cellulose (HPMC), CP 934 and SG. According to

the results obtained revealed that a sodium alginate gel was found to have the highest

viscosity and the maximum bioadhesive strength by the in vitro evaluation. HPMC

gel base showed the maximum miconazole release through both cellulose membrane

and rabbit skin at pH 4.75, while sodium alginate showed the lowest release rate.

Sumit Chabra et al., (2007) prepared Phase-sensitive in situ gel forming

controlled release formulations of lysozyme which was prepared using poly lactic acid

(PLA) and/or poly glycolic acid (PGA) based polymers differing in end groups in

addition to composition, and a solvent system consisting of various ratios of benzyl

benzoate (BB) and benzyl alcohol (BA). Formulations were prepared with carboxylic

acid group polymers showed significantly (p < 0.05) lower burst release (4%) than

those containing ester end groups (20–30%). Nonetheless, formulations consisting of

polymer with carboxylic acid end groups showed significantly (p < 0.05) faster release

rate of incorporated lysozyme.

Hatefi et al., (2002) gave an account on ability to inject a drug incorporated

into a polymer to a localized site and have the polymer form a semi-solid drug depot

has a number of advantages. Between these advantages is ease of application and

localized, prolonged drug delivery. For these benefit a large number of in situ setting

polymeric delivery systems have been developed and investigated for use in

delivering a wide variety of drugs.The various strategies that have been used to

formulate in situ setting systems, and outline their merits and demerits as localized

drug delivery systems.

Yuri Jeong et al., (2009) reported a poly (ethylene glycol)-block-poly

(alanine-co-phenyl alanine) (PEG-PAF) aqueous solution that undergoes solution-to-

gel transition as the temperature increases. The temperature induced sol-to-gel

transition was observed at as low a concentration as 3.0–7.0 wt. %. In this system

micellar aggregation accompanying small conformational changes of the peptide from

random coils to β-sheets is suggested as the sol-to-gel transition mechanism of the

PEG-PAF aqueous solution. The recent functional polypeptide may be very promising

as an in-situ gelling system for tissue engineering, cell/stem cell therapy, and drug

delivery.

Marie Sherlund et al., produced thesis on local anesthetic formulations based

on PEO-PPO-PEO block copolymers (PEO and PPO being polyethylene oxide) and

polypropylene oxide), respectively) or nonionic cellulose ethers undergoing

temperature- or dilution-induced thickening were investigated. The critical

micellisation and gelation temperatures of the systems were found to be

interconnected and influenced by the total polymer concentration and the polymer

mixture composition, as well as the presence of co solutes and pH.A less-viscous

isotropic phase that turns into a more-viscous hexagonal phase as the water content

increases was found by combining Lutrol® F68, water, a eutectic mixture of lidocaine

and prilocaine and Akoline MCM. The system has a slower release rate compared to

the microemulsion formulation, which might make it suitable for indications where a

longer duration is needed. Conclusively, a temperature-induced gelling system was

achieved by adding lidocaine and prilocaine to mixtures of ethyl (hydroxyethyl)

cellulose (EHEC) and sodium dodecyl sulfate (SDS), hexadecyltrimethylammonium

bromide (CTAB) or myristoylcholine bromide systems at or just below the surfactant

concentration found to give a maximum viscosity increase at room temperature. In

particular, the myristoylcholine bromide system may be interesting considering its

antibacterial properties and biodegradability.

Ulrike Bertram et al., (2006) reported the preparation and characterization of

sponge-like, in situ gelling inserts based on bioadhesive polymers. Water loving

polymers like (carrageenan, Carbopol, chitosan, hydroxypropyl methylcellulose

(HPMC) K15M and E5, sodium alginate, sodium carboxy methylcellulose (NaCMC),

polyvinyl pyrrolidone (PVP) 90, and xanthan gum) were dissolved with/without the

model drug oxymetazoline HCl in demineralized water and lyophilized into small

inserts. The drug release from insert system prepared from high molecular weight

polymers (carrageenan, Carbopol, chitosan, HPMC K15M, NaCMC, xanthan gum)

was a complex interplay of osmotic forces, water uptake and electrostatic interactions

between drug and polymer. The drug release lowered with higher polymer content

and increased drug loading of the insert. Mucoadhesive nasal inserts have a high

potential as new nasal dosage form for extended drug delivery.

The aim of Wen-Di Ma et al., (2008) was to prolong the precorneal resident

time and improve ocular bioavailability of the drug; Pluronic F127-g-poly (acrylic

acid) copolymers were studied as in situ gelling vehicle for ophthalmic drug delivery

system. The viscosity behavior and in vitro drug release of Pluronic-g-PAA

copolymer in situ gel were investigated. The rheogram and in vitro drug release

studies indicated that the drug release rates decreased as acrylic acid/Pluronic molar

ratio and copolymer solution concentration increased. But the drug concentration had

no clear effect on drug release. In vivo studies showed the drug resident time and the

total resident amount in rabbit‘s conjunctivae sac increased by 5.0 and 2.6 folds for in

situ gel, compared with eye drops.

Li Gan et al., (2009) designed a novel microemulsion in situ electrolyte-

triggered gelling system for ophthalmic delivery of a lipophilic drug, cyclosporine A

(CsA). A CsA-loaded microemulsion was formulated using castor oil, Solutol HS 15

(surfactant), glycerol and water.(CsA) microemulsion was then dispersed in a

Kelcogel®

solution to form the final microemulsion in situ electrolyte-triggered

gelling system. In vitro, the viscosity of the CsA microemulsion Kelcogel®

system

improved dramatically on dilution with artificial tear fluid and exhibited pseudo-

plastic rheology. In vivo results revealed that the AUC0→32h of corneal CsA for the

microemulsion Kelcogel®

system was approximately three-fold greater than for a CsA

emulsion. Moreover, at 32h after administration,

As per Hongyi Qi et al., (2007) conventional ophthalmic solutions often

eliminate rapidly after administration and cannot provide and maintain an adequate

concentration of the drug in the precorneal area. To resolve these problems, we

developed a thermosensitive in situ gelling and mucoadhesive ophthalmic drug

delivery system containing puerarin based on poloxamer analogs (21% (w/v)

poloxamer 407/5% (w/v) poloxamer 188) and carbopol (0.1% (w/v) or 0.2% (w/v)

carbopol 1342P NF). The combined solutions would convert to semisolid gel depot

under physiological condition and attach to the ocular mucosal surface for a relative

long time. The addition of carbopol 1342P NF not only did not affect the

pseudoplastic behavior with hysteresis of the poloxamer analogs solution and leaded

to a higher shear stress at each shear rate, but also enhanced the mucoadhesive force

significantly. In vitro drug release studies demonstrated diffusion-controlled release of

puerarin from the combined solutions over a period of 8 h.

Zhidong Liu et al., (2006) reported the poor bioavailability and therapeutic

response exhibited by conventional ophthalmic solutions due to rapid pre-corneal

elimination of the drug may be overcome by the use of in situ gel-forming systems that

are instilled as drops into the eye and then undergo a sol–gel transition in the cul-de-sac.

The present work describes the preparation and evaluation of an ophthalmic delivery

system of an antibacterial agent, gatifloxacin, based on the concept of ion-activated in

situ gelation. Sodium alginate (Kelton®) was used as the gelling agent in combination

with HPMC (Methocel E50Lv) which acted as a viscosity-enhancing agent. The

viscosity behaviors of all formulations were not affected by the incorporation of

gatifloxacin.

Kunihiko Itoh

et al., (2008) has examined the gelation and release

characteristics of mixtures of xyloglucan, which has thermally reversible gelation

characteristics, and pectin, the gelation of which is ion responsive, with the aim of

formulating an in situ gelling vehicle suitable for oral sustained drug delivery. An

analysis of the effect of the inclusion of pectin (0.75% (w/w)) on the viscosity behavior

of gels formed from solutions of xyloglucan (1.5 and 2.0% (w/w)) showed a

significantly greater gel strength when pectin was present in the formulation. The in

vitro release of para amio phenol from gels containing 1.5% (w/w) xyloglucan, and

1.5 or 2.0% (w/w) xyloglucan/0.75% (w/w) pectin was diffusion-controlled.

Measurement of plasma levels of para amio phenol after oral administration to rats of a

solution containing 1.5% (w/w) xyloglucan and 0.75% (w/w) pectin showed that a

more sustained release and higher drug bioavailability was achieved from the gels

formed by the in situ gelation of this preparation compared to that of a 1.5% (w/w)

xyloglucan solution; 0.75% (w/w) solutions of pectin did not form gels under these

conditions. Visual observation of the contents of the rat stomach at intervals after oral

administration showed that the inclusion of pectin in the xyloglucan solutions was

successful in reducing gel erosion, so prolong drug release.

Miyazaki et al., (2001) reported the prolonged residence of drug formulation

in the nasal cavity is of utmost importance for intranasal drug delivery. The plan of

the present work was to develop a mucoadhesive in situ gel with reduced nasal

mucociliary clearance in order to improve the bioavailability of the antiemetic drug,

metoclopramide hydrochloride (MCP HCl). The thermosensitive in situ gel gelation

upon contact with nasal mucosa was conferred via the use of the thermoensitive

gelling poloxamer 407 whereas bioadhesion and drug release enhancement were

modulated via the use of mucoadhesive and polyethylene glycol (PEG) polymers

respectively. The preparation with favorable sol–gel gelation n temperatures (25–

32◦C) and high in vitro drug release (100% release in 60min) were also rheologically

stable upon storage. The bioadhesive test was performed in vivo in rats, results

showed that the carbopol-containing in situ gel prolonged the mucociliary transport

time from 10min (control solution) to 52min (mucoadhesive gel) and maintained

nasal mucosal integrity after 14-days application.

According to Srividya et al., (2001) the poor bioavailability and therapeutic

response exhibited by conventional ocular solutions due to rapid precorneal

elimination of the drug may be overcome by the use of in situ gel- systems that are

instilled as drops into the eye and undergo a sol–gel transition in the cul-de-sac. The

objective of work describes the formulation and evaluation of an ophthalmic delivery

system of an antibacterial agent, ofloxacin, based on the concept of pH sensitive in

situ gelation. Polyacrylic acid (Carbopol 940) was used as the gelling agent in

combination with hydroxypropylmethylcellulose (Methocel E50LV) which acted as a

viscosity increasing agent. The developed preparation was therapeutically efficacious,

stable, and non-irritant and provided prolong release of the drug over an 8-h period.

The developed system is thus a viable choice to conventional eye drops.

The aim of Katrin Moebus et al., (2009) was to prepare and evaluate a novel

hydrogel-based delivery systems allowing for the controlled release of drugs to

mucosal surfaces.Terbutaline sulfate and bovine serum albumin (BSA)-loaded sodium

alginate-poloxamer microparticles were formulated by a w/o-emulsion- and external

gelation method. The microparticles were evaluated by optical and scanning electron

microscopy, laser light diffraction, atomic absorption spectroscopy, energy-dispersive

X-ray analysis, via complexation with 1, 9-dimethyl methylene blue and using

dialysis membrane bags as well as modified Franz diffusion cells for in vitro drug-

release measurements.

Koffi et al., (2006) aimed at providing a thermosensitive gels based on

poloxamer 407, a thermosensitive polymer, and hydroxypropylmethylcellulose

(HPMC), a bioadhesive polymer, intended for the rectal delivery of quinine in

children. Investigation on the rabbit rectal mucous membrane, founded on a technique

of traction of the adhesive/adhered joint, made it possible to characterize the

bioadhesive properties of the gels.

Yajaman Sudhakar et al., (2006) reported the rapid developments in the field

of molecular biology and gene technology reported in generation of many

macromolecular drugs including peptides, proteins, polysaccharides and nucleic acids

in great number possessing superior pharmacological efficacy with site specificity and

devoid of untoward and toxic effects. Nonetheless, the main impediment for the oral

delivery of these drugs as potential therapeutic agents is their extensive presystemic

metabolism, instability in acidic environment resulting into inadequate and erratic oral

absorption.

Byeongmoon Jeong et al., (2002) gave an account on aqueous polymer

solutions that are transformed into gels by changes in environmental conditions, such

as temperature and pH, thus resulting in in situ hydrogel system formation, have

recently attracted the attention of many investigators for scientific interest and for

practical biomedical or pharmaceutical applications. When the hydrogel is formed

under physiological stimuli and maintains its integrity for a desired period of time, the

process may provide various merits over conventional hydrogels. Because of the

simplicity of pharmaceutical preparation by solution mixing, biocompatibility with

biological systems, and convenient administration, the pharmaceutical and biomedical

uses of the water-based sol–gel induced system include solubilization of low-

molecular-weight hydrophobic drugs, controlled release, labile biomacromolecule

delivery, such as proteins and genes, cell immobilization, and tissue engineering.

When the formed gel is proven to be biocompatible and biodegradable, producing

non-toxic degradation products, it will provide additional benefits for in vivo

applications where degradation is desired. It is timely to condense the polymeric

systems that undergo sol–gel transitions, particularly due to temperature, with

emphasis on the underlying transition mechanisms and potential delivery aspects.

This review stresses the polymeric systems of modified natural polymers, N-

isopropylacrylamide copolymers, poly (ethylene oxide)/poly (propylene oxide) block

copolymers, and poly (ethylene glycol)/poly (D, L-lactide-co-glycolide) block

copolymers.

Helene Hagerstrom et al., (2000) gave a rheological method to measure

bioadhesion. Mucoadhesion was evaluated for two ion-sensitive polymers, Carbopol

934 and Gelrite (deacetylated gellan gum), in a simulated physiological environment

using two commercially available mucins. The method simulates the interpenetration

layer in the bioadhesion process. The elastic modulus for a polymer/mucin mixture is

compared with the elastic modulus for the polymer alone, and an increase in the

elastic modulus for the mixture compared to the polymer is interpreted as a positive

interaction caused by bioadhesion. In this study ion induced of polymer concentration,

type of mucin and experimental rheological factors, such as gap width, were

examined. The choice of polymer concentration was critical, especially with the

porcine gastric mucin. We found that one is more likely to obtain positive interactions

with weak gels. It was also shown that the choice of mucin has a large influence on

the results obtained. Carbopol 934 interacted more strongly with the bovine sub

maxillary gland mucin than with the porcine gastric mucin, whereas the gel structure

of gellan gum was destroyed when mixed with the bovine mucin., additionally, it was

concluded that with hydrogels consisting of gel particles (such as CP 934),

rheological measurements can give highly varying results, depending on, for example,

the concentration and ion-sensitivity of the polymer, the quantity of ions present, as

well as the gap width of the measuring system.

As per Claudia Valenta et al., (2005) reviewed the mucoadhesive polymer-

systems for vaginal route of administration of drugs. Besides locally acting drugs it is

also of importance for systemic drug delivery, uterine targeting or even vaccination.

Presently available dosage forms have several limitations, therefore novel concepts

and dosage forms are needed. In this field mucoadhesive polymers will play a major

role. following discussion of the anatomy and physiology of the vagina this review

highlights the most important studies based on mucoadhesive polymer-systems like

poly (acrylates), chitosan, cellulose derivatives, hyaluronic acid derivatives, pectin and

traganth, starch, poly (ethylene glycol), sulfated polysaccharides, carrageenan, Na-

alginate and gelatine.

Shozo Miyazaki et al., (2005) examined the influence of polyhydric alcohols

(taste masking agents) on the rheological properties of in situ gelling pectin

formulations and on the in vitro and in vivo release of paracetamol and ambroxol from

these formulations. Gelation of orally administered pectin solutions containing

calcium in complexes form occurred on release of calcium in the acidic environment

of the stomach. Inclusion of 10% (w/v) sorbitol in 2% (w/v) pectin sols reduced the

viscosity and ensured Newtonian flow properties. Xylitol and mannitol in paralled

concentrations were less effective in reducing viscosity; sucrose increased viscosity

and caused non-Newtonian flow. The in vitro release of paracetamol from 2% (w/v)

pectin gels formulated with 10% (w/v) of sorbitol, erythritol, xylitol or mannitol, and

of ambroxol from 2% (w/v) pectin gels containing 10% (w/v) sorbitol, followed

diffusion-controlled kinetics. Pectin gels (2%, w/v) containing sorbitol (10%, w/v)

sustained the release of paracetamol in the rat stomach and bioavailabilities of

approximately 90% of those from an orally administered paracetamol syrup were

achieved. prolong release of ambroxol from in situ gelling formulations was achieved

with pectin concentrations of 1.5 and 1% (w/v) and a sorbitol concentration of 10%

(w/v).

Jung Yun Chang et al., (2002) reported that timely gelation and retention of

in situ-gelling vaginal formulations would be fundamental to improve the efficacy of

drugs. In this study, different rheological properties of clotrimazole gels were

evaluated for predicting their performance in vagina. Two kinds of thermosensitive

and mucoadhesive formulations were composed of poloxamer 407 (P407, 15%),

polycarbophil (0.2%), and different amounts of P188 (15 vs. 20%). Both formulations

were Newtonian at 20 °C but non-Newtonian at 37 °C. Although both liquid

preparations gelled below the vaginal temperature, they differed in gelation time and

viscoelastic properties in the presence of vaginal fluid stimulant. At body temperature,

the formulation with 20% of P188 gelled within 35 s but it took two times longer for

the other one gelled. Upon dilution with simulated vaginal fluid, the formulation with

20% of P188 retained the rheology of a gel, but the other one lost the viscoelastic

properties typical for a gel. In addition, after dilution with simulated vaginal fluid, the

elastic modulus was orders of magnitude higher in the formulations with 20% of P188

relative to the other one. These final results indicate that the rheological evaluation at

the physiologic conditions needs to be preceded to develop more effective in situ-

gelling vaginal formulations.

Mako et al., (2009) studied the formulation and examination of a novel

thermo responsive and bioadhesive, in situ gelling drug delivery system, which can be

used in the treatment of oesophageal pain and inflammation. A bioadhesive cellulose

derivative (Metolose® 60SH) was used as a thermo responsive material, because

Metolose® has thermal gelation properties at certain temperature. The thermal gela-

tion temperature (T2) of Metolose® 60SH 2 w/w% solution is above body

temperature (65-66 °C), but by using different methods (Metolose® 60SH

concentration, auxiliary materials), it can be shifted near to body temperature. The pH

alteration between pH = 2-10 and the application of different alcohols did not

motivate the gelation temperature, but using water-soluble salts and changing the

concentration of Metolose® 60SH solution between 2 and 3 w/w% the thermal

gelation point could be decreased. Different NSAIDs were used as model drugs and

which had not influence on thermal gelation temperature, but difference in in vitro

liberation and penetration can be observed. In vitro mucoadhesion test pointed out

that the condition of investigated membrane can change the adhesion. Morphological

test of esophageal tissue showed that investigated materials had no irrigative or tissue-

damaging effect on the esophageal mucosa even after 12 h.

Sham Badgujar et al., (2010) Improved the nasal retention time of

Sumatriptan succinate by formulating as in situ mucoadhesive gel by using Pluronic

PF127 and carbopol 974P. The prepared in-situ gel was evaluated for gelation

temperature, drug content, mucoadhesive force, gel strength and viscosity

measurement. Further in situ gels prepared with and without permeation enhancer

(Fulvic acid) were evaluated for its In vitro drug diffusion study by Fran‘s Diffusion

Cell. The data of In vitro drug diffusion study of in situ gel prepared with and without

permeation enhancer showed non Fickian or anomalous diffusion mechanism.

Faroongsarng, Sukonrat et al., (2008) reported that in a polymer-water

matrix, freezable water is depressed due to either porosity confinement or interaction.

The preferred starch- and cellulose-based polymers including pre-gelatinized starch

(PS), SG, sodium starch glycolate, hydroxy propyl methyl cellulose (HPMC), sodium

carboxymethyl cellulose, and croscarmellose sodium were employed. The pre-treated

with ambient humidity (85-100% relative humidity, at 30.0 ± 0.2 °C for 10 days) and

with excess water (hydrogels) samples were subjected to between 25 and 150 °C

cooling-heating cycle at 5.00 °C/min rate. The volume fractions of hydrogels were

measured by light scattering technique. It was experimental that all polymers but PS

and HPMC with ambient humidity presented freezable water in two distinct fractions

namely bound water where crystallizing/melting temperature was depressed and bulk

water. The water transition in samples with various contents exhibited the pattern as a

polymer solution, thus rather than confinement, the depression was due to interaction.

Yang et al., (2009) formulated docetaxel (DTX) into an injectable thermo-

sensitive mixed micelle gel (MMG). It was investigated that the mixed micelle

composed of Pluronic F127 (PF127) and Tween 80 overcame the problem of PF127

micelle on physical stability and drug release due to the low solubilization capacity of

PF127 for the high lipophility of DTX molecules. They proved that this injectable

MMG system provided a promising locally delivered vehicle for hydrophobic anti-

tumor agents to increase their efficacy and thereby improved their therapeutic effect

for clinical treatment.

By Cao et al., (2007) a novel copolymer, poly (N-isopropylacrylamide)–

chitosan (PNIPAAm–CS), was investigated for its thermal sensitivity in situ gel

system properties and potential utilization for ocular drug delivery. The thermal

sensitivity and low critical solution temperature (LCST) were determined by the cloud

point method. PNIPAAm–CS had a LCST of 32 °C, which is close to the surface

temperature of the eye. The in vivo ocular pharmacokinetics of timolol maleate in

PNIPAAm–CS solution were evaluated and compared to that in conventional eye drop

solution by using rabbits according to the microdialysis method. The Cmax of timolol

maleate in aqueous fluid for the PNIPAAm–CS solution was 11.2 μg/ml,which is two-

fold higher than that of the conventional eye drop, along with greater AUC.

Additionally, the PNIPAAm–CS gel-forming solution of timolol maleate had a stronger

capacity to reduce the intra-ocular pressure (IOP) than that of the conventional eye

drop of same concentration over a period of 12 h. In addition, the MTT assay showed

that there is little cytotoxicity of PNIPAAm–CS at concentration range of 0.5–400

μg/ml. These results suggest that PNIPAAm–CS is a potential thermosensitive in situ

gel-forming material for ocular drug delivery, and it may improve the bio-availability,

efficacy, and compliance of some eye drugs.

Chun et al., (2003) studied a polymeric film composed of carbopol,

poloxamer and hydroxypropyl methylcellulose which were prepared to develop a

buccal patch and the effects of composition of the film on adhesion time, swelling

ratio, and dissolution of the film .The prosperity of penetration enhancers on the

release of triamcinolone acetonide (TAA) were also studied. The H bonding between

corbomer and poloxamer played important role in reducing swelling ratio and

dissolution rate of polymer film and increasing adhesion time. The swelling ratio of

the composite film was significantly decreased and the adhesion time was increased

when compared with carbopol film. When the ratio of pluronic to HPMC increased

from 0/66 to 33/33, the release rate of triamcinolone acetonide decreased. However,

no further significant decrease of release rate was observed beyond the ratio of 33/33.

The release rate of triamcinolone acetonide in the polymeric film containing

polyethylene glycol 400, a plasticizer, showed the highest release rate followed by

triethyl citrate, and castor oil. The drug release rate of triamcinolone acetonide from

the polymeric film containing permeation enhancers was slower than that from the

control without enhancers. From these result it was clear that buccal patch composed

of polymeric film of cabopol, poloxamer and hydropropyl methylcellulose was

effective in the buccal delivery of triamcinolone acetonide.

Claudia Valenta et al., (2005) reported that vagina is an important area of the

reproductive tract and serves as a potential route of drug administration. Besides

locally acting drugs it is also of importance for systemic drug delivery, uterine targeting

or even vaccination. Recently available dosage forms have several limitations,

therefore novel concepts and dosage forms are needed. In this field bioadhesive

polymers will play a major role. After discussion of the anatomy and physiology of the

vagina this review highlights the most important studies based on bioadhesive polymer-

systems like poly (acrylates), chitosan, cellulose derivatives, hyaluronic acid

derivatives, pectin and tracanth, starch, poly (ethylene glycol), sulfated

polysaccharides, carrageenan, sodium alginate and gelatine.

According to Madan et al., (2010) in situ forming polymeric formulations are

drug delivery systems that are in sol form before administration in the body, but once

administered, undergo gelation in situ, to form a gel. The formation of in situ gel

depends on factors like temperature modulation, pH change, presence of ions and

ultra violet irradiation, from which the drug gets released in a sustained and controlled

manner. Different polymers that are used for the formulation of in situ gels include

gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly (DL-lactic acid), poly

(DL-lactide-co-glycolide) and poly-caprolactone. The selection of solvents like water,

dimethylsulphoxide, NMP, triacetin and 2-pyrrolidone for these formulations depends

on the solubility of polymer used. Mainly in situ gels are administered by oral, ocular,

rectal, vaginal, injectable and intraperitoneal routes. The in situ gel system polymeric

formulations offer several merits like prolonged action in comparison to conventional

drug delivery systems. The article presents a detailed review of these types of

polymeric systems, their evaluation, advancements and their commercial

formulations. From a formulation point of view, the production of such devices is less

complex and thus lowers the investment and manufacturing cost.

Shin et al., (2000) developed the mucoadhesive gels with the use of carbopol

934 and pluronic F127. The drug release profiles of drug were studied as the function

of drug concentration and temperature. Bile salts, glycols and non-ionic surface active

were used as enhancer for effective permeation through buccal mucosa. Between

these enhancers sodium deoxycholate is used as most excellent enhancer. The

poloxamer F127 and CP 934 can be used as a reservoir which release triamcinolone

acetonide or other drugs when applied topically by forming soft bioadhesive gel at

body temperature.

Himanshu gupta et al., (2010) have developed and optimized a chitosan

(bioadhesive and permeation enhancer) and gellan gum (ion activated gelling

polymer) based in situ gel system of clindamycin for vaginal application. The

developed formulation is thus a viable alternative to conventional vaginal dosage

forms.

Kawasaki et al., (1999) studied the potential, as sustained release vehicles,

of gels formed in situ following the oral administration of dilute aqueous solutions of

a xyloglucan polysaccharide derived from tamarind seed has been assessed by in vitro

and in vivo studies. Aqueous solutions of xyloglucan that had been partially degraded

by P-galactosidase to eliminate 44% of galactose residues formed rigid gel system at

concentrations of 1.0 and 1.5% w/w at 37°C. The in vitro diffusion of indomethacin

and diltiazem from the enzyme-degraded xyloglucan gels followed root-time kinetics

over a period of 5 h at 37°C at pH 6.8. Plasma concentrations of indomethacin and

diltiazem, after oral administration to rats of chilled 1% w/w aqueous solutions of the

enzyme-degraded xyloglucan containing dissolved drug, and a suspension of

indomethacin of the same concentration were compared. Study indomethacin plasma

concentrations were noted from both formulations after 2 h and were maintained over

a period of at least 7 h. Indomethacin bioavailability from xyloglucan gels formed in

situ was lowered approximately threefold compared with that from the suspension.

The outcome of this study suggests the potential of the enzyme-degraded xyloglucan

gels as vehicles for oral delivery of drugs.

Bourre et al., (2000) made an attempt to develop a 5-aminolevulinic acid

(ALA) thermosetting gel composed of pluronic F127 gel. The evaluation of

preparation was done in an in vivo mouse model for potential use in photodynamic

therapy of Barrett‘s mucosa. In vitro studies of the influence of poloxamer F127

percentage on thermosetting gel temperature, followed by the influence of ALA

concentration on thermosetting temperature and 5-aminolevulinic acid -gel stability as

a function of time or temperature were studied. In vivo relationships between 5-

aminolevulinic acid doses and fluorescence were studied to determine the optimal

concentration. Fluorescence measurement in invivo studies showed that 5-

aminolevulinic acid concentration and time had a nonlinear influence on

protoporphyrin IX synthesis. 5-aminolevulinic acid-poloxamer F127 is a suitable

formulation for treatment of Barrett‘s esophagus, allowing easy application in liquid

form at 4C and good adhesion in the esophagus in gel form, with efficient diffusion of

ALA into treated mucosa.

Mehta et al., (2009) investigated the in situ gelling systems based on

temperature-dependent phase transition containing pheniramine and phenylephrine

which were developed using combination of Poloxamers, different cellulose polymers

(HPMC) and XG. In vitro release studies revealed significant prolonged released of

both drugs up to 24 h as against only 2 h with drug solution preparation were found to

stable over period of 3 months. In vivo studies of nasal residence time of in situ gel by

gamma scintigraphy was found to be significantly higher (6 h) in comparison to drug

solution (15 min). It can be resulted that Poloxamers in combination with HPMC are

suitable to develop stable, safe in situ temperature-based mucoadhesive gelling

systems with prolonged nasal residence time.

Bhalerao et al., (2009) designed a nasal bioadhesive in situ gel system of

ondansetron which is a serotonin receptor antagonist used in the management of

nausea and vomiting that is associated with cancer chemotherapy. There is a need for

nasal delivery due to poor bioavailability of drug because of first pass effect. The aim

of this study was to develop an intranasal delivery system of ondansetron Hcl using

thermo induced polymer PF127 and mucoadhesive polymer hydroxypropylcellulose.

Due to enhance in bioadhesive polymer concentration, there was raise in bioadhesion

strength, at the same time there was decrease in the spreadability. An in vitro

diffusion study revealed that viscosity of the vehicle has an influence on drug. The

release of ondansetron Hcl from the gel matrix showed diffusion- controlled.

Hokett SD., (2000) studied the Pluronic polyol effects on Human Gingival

Fibroblast (HGF) attachment and growths. The objective of this study was to

determine the in vitro effects of pluronic polyols, a family of broadly used surfactants

currently used as drug carriers for antibiotic, anti-inflammatory, and antineoplastic

agents, on the attachment and growth of human gingival fibroblasts (HGF) to dentin

and plastic surfaces using established tissue culture techniques. Plastic culture wells

containing Eagle's minimal essential media (EMEM) with 10% fetal calf serum and

poloxamer F68 or F127 in concentrations from 1.2 x 10(-2) to 1.2 x 10(-10) M were

incubated with Human Gingival Fibroblast and run in replicates of ten. Attached cells

were quantified by measuring the optical density of methylene blue-stained cells. The

report thus showed that pluronic was beneficial in the very low amount of dosages in

early post-surgical wound healing by facilitating early attachment and increasing the

growth rate of human gingival fibroblasts.

orishita et al., (2001) studied the release of insulin from poloxamer F127 (PF

127) gel composed of unsaturated fatty acids such as oleic acid (18:1),

eicosapentaenoic acid (20:5) or docosahexaenoic acid (22:6) and the hypoglycemic

effect of insulin following the buccal administration of the gel formulations in normal

rats. A weighed amount of poloxamer F127 was slowly added to a cold (5–10°C)

phosphate buffer solution of pH 7.4, mix it until there was complete dissolution of the

polymer. Insulin (porcine insulin, 27.0 IU: mg) was dissolved in 0.1 N HC1, then

diluted with phosphate buffer solution and adjusted with 0.1 N NaOH to pH 7.4. The

insulin solution was added with gentle stirring to the poloxamer F127 solution. Male

Wistar rats were used for the in vivo studies. In the presence of unsaturated fatty

acids, insulin drug release was found to be low. Remarkable and continuous

hypoglycemia was induced by all Polaxamer F127 gels.

Hiremath et al., (2008) have discussed about the problem in ocular

therapeutics and the attainment of optimal drug concentration at the site of action,

which is compromised mainly due to precorneal loss resulting in only a small amount

of the drug being ocularly absorbed. The successful dose administered may be altered

by increasing the retention time of medication into the eye by using in situ gel

forming systems. The aim of the present investigation is to formulate and evaluate

novel in situ gum based ophthalmic drug delivery system of linezolid. Hydroxypropyl

guar and xanthum gum were used as gum with the combination of hydroxyl ethyl

cellulose, (CP) and SG as viscosity enhancing agents. Suitable concentrations of

buffering agents were used to adjust the pH to 7.4. All the formulations were

sterilized in an autoclave at 121°C for 15mins. The formulations were examined for

clarity, pH measurement, gelling capacity, drug content estimation, rheological study,

in vitro diffusion study, antibacterial activity, isotonicity testing, and eye irritation

testing.

pandit, bharathi., (2007) evaluated the different types of in situ gelling

systems of idomethacin, in SG vehicle which were formulated and evaluated for their

pharmaceutical properties including viscosity, sterility and drug content uniformity.

The gelling capacity of the prepared systems was evaluated by using an in house

fabricated gellation cell. The in vitro release kinetics model of the formulated systems

was determined in simulated tears.

C.Doijad, F.V manvi., (2006) Proposed that poor bioavailability and

therapeutic response exhibited by conventional ophthalmic drops due to rapid

procorneal elimination of drug may be overcome by the use of in situ gel systems that

are instilled as drops into the eye and undergo a sol-gel transition in the sac. They

described the preparation and evaluation of an ocular delivery system of an

antibacterial agent, gatifloxacin, based on the concept of ion activated system.

Jelvehdari et al., (2006) Studied that the gel dosage forms could be

successfully used as drug delivery systems considering their ability to control drug

release and to protect medicaments from a hostile environment. The objective of their

work was to examine the properties of CP 934 polymeric system in water-miscible

cosolvents such as glycerin and alcohol. Drug like Benzocaine is a local anesthetic

and the mucoadhesive gel formulation is applied in the treatment of dental pain.

Samples were prepared by simply dispersing different amounts of CP 934 (0.5-3%)

into the alcoholic solution at the room temperature and were kept at 4, 25 and 40 °C.

All these systems were then characterized for distribution, mucoadhesive on the

mucosa, physical stability and drug release. The silastic membrane was employed.

Franz diffusion cell used to study in vitro drug release. The increase in carbopol

concentration caused increased viscosity and bioadhesive. Neutralization of pH in

various concentrations of carbopol gels showed resulted in high viscosity. A

relationship between the viscosity and bioadhesive strength was shown in the

neutralized CP 934gels.

Varsha Gaikwad et al., (2010) investigated a mucoadhesive in-situ gel

preparation which was developed with an aim to decrease the mucociliary clearance

by using mucoadhesive polymer in gel, thereby increasing the contact of formulation

with nasal mucosa membrane and hence improving the absorption of drug. The in situ

gelation was achieved by the use of poloxamer F127, which exhibit thermoreversible

gelation property. The preparation additives are having effect on thermodynamic of

phase transitions at gelation (T1) and gel melting (T2) temperature. Result discovered

that addition of bioadhesive polymer CP 934 has decreased T1 whereas addition of

PEG400 increased T1 and also PEG400 increased in- vitro drug release. In- vitro drug

release shows that with increasing carbopol concentration increases viscosity of

formulation and influences the diffusion of drug particle while addition of PEG 400

enhances in vitro drug release.

Charyulu Narayana et al., (2009) designed and evaluated in situ vaginal gels

of secnidazole, based on ion activated systems. The ion induced system utilizes

polymers that exhibit sol-to-gel phase transition due to change in specific physico

chemical parameters. Ion triggered system using gellan gum (0.1-0.75％ w/v) along

with sodium carboxy methyl cellulose was used to prolong the release of secnidazole

(1％ w/v). Preparations were evaluated for gelling capacity, viscosity, gel strength,

mucoadhesive force, spreadability, microbiological studies and in vitro release

studies. The transformations of sols occur in the presence of monovalent/divalent

cations in the dissolution medium. Erect of calcium carbonate and other process

parameters were optimized and found that increase in calcium ions produce stronger

gels.

El laithy

and El-Shaboury., (2002) investigated the influence of the vehicle

on the release and permeation of fluconazole, a topical antifungal drug dissolved in

Jojoba oil. Series of Cutina lipogels (Cu-tina CPA [cetyl palmitate], CBS [mixture of

glyceryl stearate, cetearyl alcohol, cetyl palmitate, and cocoglyc-erides], MD

[glyceryl stearate], and GMS [glyceryl monostearate] in different concentrations as

well as gel microemulsion were prepared. In-vitro drug release in Sorensen's citrate

buffer (pH 5.5) and permeation through the excised skin of hairless mice, using a

modi-fied Franz diffusion cell, were performed. The viscosity behavior and the

apparent viscosity values for different gel bases were measured before and after

storage under freezing conditions at -4 °C and were taken as measures for stability of

network structure. Candida albican was used as a model fungus to evaluate the anti-

fungal activity of the best formula achieved. The outcome of in vitro drug release and

its percutaneous absorption showed that the highest values from gel microemulsion

were assured. The viscosity behavior of the prepared lipogel systems showed

pseudoplastic (shear-thinning) flow indicating structural breakdown of the existing

intermolecular interactions between polymeric chains. Moreover, the stability study

discovered no significant difference between viscosity before and after storage for

different formulae except for CPA Cutina lipogel (using analysis of variance

[ANOVA] test at level of significance .05). The antifungal activity of fluconazole

drug showed the widest zone of inhibition with gel microemulsion. The lipogel

microemulsion is a brilliant vehicle for fluconazole topical drug delivery.

Li et al., (2006) aimed at providing a Guar gum/poly (acrylic acid) semi-

interpenetrating polymer network (IPN) hydrogels which had been prepared via free

radical polymerization in the presence of a crosslinker of N, N 0-methylene

bisacrylamide (MBA). The kinetics model of swelling and the water transport

mechanism were studied as a function of the composition of the hydrogels and the pH

of the swelling medium. Hydrogels showed massive swelling in aqueous medium and

displayed swelling characteristics.

Datta & Bandyopadhyay et al., (2005) investigated a new nasal drug

delivery system of diazepam with a natural mucoadhesive agent from fenugreek

(Trigonella foenum-graecum L). Excised bovine nasal membrane of this natural

bioadhesive agent was found to be elevated in comparison to synthetic polymers,

hydroxy propyl methyl cellulose and CP 934, which are conventionally used for

similar purpose. This patient responsive, needle free dosage form may replace

the diazepam injections in future.

Tarawneh et al., (2005) studied Ciclopirox olamine (CPO) metal complexes

which have been formulated and characterized using elemental analysis, infra red

(IR), melting point and differential scanning calorimetry (DSC). Spectroscopic

titration using molar ratio method indicated the occurrence of 1:1 complexes for

Ciclopirox olamine with almost all the examined metals. Ciclopirox olamine

properties were also studied including aqueous solubility and apparent partition

coefficient. Report showed that generally complex formation dramatically decreased

the solubility and increased apparent partition coefficient. However, some metal

complexes exhibited opposite effect. Finally the complex formation can modify the

solubility and apparent partition coefficient, which may suggest the use of complexes

to manipulate the physicochemical properties of the drug.

Burgess et al., (2000) evaluated the pharmacodynamic activity of fluconazole,

itraconazole, and amphotericin B against Candida albican. Susceptibilities were

resolute according to the NCCLS guidelines (M27). Time-kill studies were performed

using antifungal concentrations of 0.25–32 3 MIC. Samples were withdrawn at

predetermined time points and then plated using a spiral plater. Colony counts were

determined after incubation at 35°C for 24 h. The AUKC0–48 was plotted against the

concentration/MIC ratio. Candida isolates (95-2672, 96-15, and 95-2542) were

classified as susceptible, susceptible-dose dependent, and resistant to fluconazole and

itraconazole (MIC 5 0.25 and 0.03 mg/mL, 32 and 0.5 mg/mL, 64 and 1 mg/mL;

respectively). All three isolates were susceptible to amphotericin B (MIC 5 0.13

mg/mL). Anti fungal drug of Fluconazole inhibited the growth of the susceptible and

S-DD isolates and was ineffective at all concentrations against the resistant isolate.

Itraconazole, on the other hand, inhibited growth of the susceptible isolate, but was

ineffective for the S-DD and resistant isolates. Maximal effectiveness was noted at the

concentration 8 3 MIC and 2 3 MIC for fluconazole and itraconazole, respectively.

Amphotericin B established concentration-dependent antifungal activity.

Groll et al., (2002) proposed the safety, pharmacokinetics, and

pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension which

were investigated in an open sequential dose escalation study with 26 human

immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old;

mean CD4-cell count, 128/l) with oropharyngeal candidiasis (OPC). Patients received

cyclodextrin itraconazole at either 2.5 mg/kg of body weight once a day (QD) or 2.5

mg/kg twice a day (BID) for a total of 15 days. Cyclodextrin itraconazole sampling

was performed after the first dose and for up to 120 h after the last dose, and

antifungal efficacy was examined by standardized scoring of the oropharynx.

Johnson et al., (2008) investigated the susceptibility of 1763 yeast isolates

(from 22 species and seven genera) using Clinical and Laboratory Standards Institute

M27-A2 microdilution methodology. Candida spp. predominated (97.1%), mainly C.

albicans (51.4%), C. glabrata (16.4%) and C. tropicalis (13.7%), followed by

Trichosporon spp. (1.1%) and Cryptococcus neoformans (1.0%). Most isolates came

from blood/catheters (72.0%) or the oesophagus/ oropharynx (11.3%). The anti fungal

drugs like voriconazole, itraconazole, fluconazole and amphotericin B MIC90 values

(minimum inhibitory concentration for 90% of the isolates) for all isolates were 1.0,

2.0, 64 and 1.0g/mL respectively. Voriconazole MICs correlated with those for

fluconazole (r = 0.91) and itraconazole (r = 0.90). Only 109 isolates (6.2%) had

voriconazole MICs ≥4.0_g/mL; all were C. albicans, C. glabrata or C. tropicalis

resistant to itraconazole (and the majority to fluconazole). Isolates from 22 patients

with amphotericin MICs ≥2.0_g/mL (range 2.0–16.0g/mL) were also cross-resistant

to one or more of the triazoles. Patients (n = 34) with voriconazole-resistant isolates

showed a 56% response to voriconazole therapy, and those patients (n = 261) with

susceptible isolates showed a 71% response.

Uzun et al., (2000) tested the in vitro activities of voriconazole, fluconazole,

itraconazole and amphotericin B against some ATCC and reference strains and 250

clinical yeast isolates. They also examined the effect of time of reading on MIC

results. Anti fungal drug of Voriconazole was the most active agent against Candida

and Trichosporon isolates, including the putatively fluconazole-resistant C. krusei

(MIC90 0.25 mg/ml) and C. glabrata (MIC 90 0.5 mg/ml). Amphotericin B MICs

were scattered in a considerably narrow range in both RPMI 1640 and Antibiotic

Medium 3. MICs at 24 hours and 48 hours were similar in general for all antifungal

tested. The maximum % of strains that showed 24-hour and 48-hour MICs within 61-

log2 dilution was observed for amphotericin B tested in RPMI (99%), and the lowest

for amphotericin B tested in Antibiotic Medium 3 (80%), anti fungal drug of

voriconazole is very effective against a wide spectrum of Candida species and 24-

hour readings could substitute 48-hour MIC evaluation.

Bevits et al., (1998) studied the safety and efficacy of oral fluconazole 150 mg

once weekly tablets and compared with those of topical clotrimazole 1% cream twice

daily in the treatment of tinea corporis, tinea cruris, tinea pedis, and cutaneous

candidiasis. A total number of 391 patients were enrolled in 19 centers in 12

countries. Treatment lasted 2 to 4 weeks for patients with tinea corporis, tinea cruris,

or cutaneous candidiasis, and up to 6 weeks for patients with tinea pedis. Fluconazole

and clotrimazole were relatively comparable in clinical outcome in nearly all

infections at the end of therapy and at the long-term follow-up visit (28 to 35 days

after the last dose). No statistically significant between group difference was observed

in the rate of eradication of the original pathogen for tinea corporls, tinea crux-is, or

cutaneous candidiasis. For tinea pedis, however, fluconazole was less effective than

clotrimazole. Safety profiles were comparable in the two treatment groups-both

agents were well tolerated with minimal adverse events.

Khanna et al., (1996) investigated the buccal adhesive erodible tablets of

clotrimazole for local delivery to the buccal cavity which were developed using

different bio-adhesive polymers along with soluble excipients like mannitol and

polyethylene glycol-6000. An apparatus simulating the in vivo conditions of the

mouth was designed in order to evaluate in vitro, the bio-adhesive performance and

release characteristics of these tablets. The in vitro mucoadhesion time and release

characteristics were found to be a function of the type of polymer and also the total

composition of the tablets. In vivo examine of placebo tablets in healthy human

volunteers indicated a linear and positive correlation between the invitro and in vivo

adhesion time.

Intini et al., (2003) prepared a series of MUC7 16-mer (residues 36-/51 of

human salivary mucin, MUC7) and histatin 5 which possess potent in vitro antifungal

activity. They have examined the efficacy of these peptides in vivo using the

experimental model of murine vulvo-vaginal candidiasis. The treatment groups

included MUC7 16-mer, histamine 5, (CT- clotrimazole), (all in poloxamer F127 gel),

and placebo (gel alone). Mice were treated intravaginally for 7 consecutive days. At

the end of the treatment, anticandidal activities were tested by colony counts and by

histological examination. All groups except CT presented positive cultures; no

statistically significant differences were found in fungal burden amongst placebo and

any treatment group except CT. Histopathological findings confirmed the

microbiological results; all groups with the exception of CT showed variable signs of

infection.

Shechtman et al., (1984) investigated a double-blind controlled study to

evaluate the effectiveness of CT in the treatment of oral candidiasis in patients with

neoplastic disease. Six of seven patients who received CT had resolution of symptoms

and signs of oral candidiasis. In five of six patients who received placebo, clinical

progression of signs and symptoms occurred, esophagitis developed, and

amphoterlcin B therapy had to be given. No toxicity was observed that could be

attributed to CT. The drug CT is effective therapy for oral candidiasis in patients with

neoplastic disease, and may prevent the development of esophagltis.

Epstein and Polsky., (1998) studied the increased use of antibiotics and

immunosuppressive agents, OPC. This infection is also linked with such advances in

medical management as chemotherapy and organ transplantation and with human

immunodeficiency virus infection. Different types of topical and systemic agents are

available to treat patients with candidiasis, but optimal management can be elusive.

Treatment of uncomplicated OPC in the immunocompetent patient involves selecting

a particular formulation of a topical medication based on oral conditions, length of

contact time, and taste, texture, and cost of the medication. Treatment of severe OPC,

particularly in patients with a compromised immune system, is often more difficult,

and relapses are common. Results of resistance to systemic agents, particularly in

patients needing recurrent therapy, are increasing. Drug like Amphotericin B, long

used as an intravenous agent, is now available as an oral suspension that may offer

therapeutic benefits comparable to those of systemic therapy without the toxicity

associated with systemic absorption.

Hoepelman., (1996) reviewed the current status of oral candidiasis which is a

common fungal infection in patients with an impaired immune system, such as those

undergoing chemotherapy for cancer and patients with acquired immunodeficiency

syndrome. It has an elevated morbidity amongst the latter group with approximately

85% of patients being infected at some point during the course of their illness. A key

predisposing factor in HIV-infected patients is a decreased CD4 T-cell count. The

majority old‘ infections are due to C. albicans although other species such as C.

glabrata, C. tropicalis, C. krusei and C. parapsilosis are increasingly isolated. Group

of systemic azoles, ketoconazole, fluconazole and itraconazole, have been an

important benefit in treatment. So far, resistance has primarily been a problem with

fluconazole in acquired immunodeficiency syndrome. Nonetheless, it is important that

measures are instituted to prevent the spread of resistant strains and the development

of cross-resistance. Even though the NCCLS has established a reference method to

measure in vitro susceptibility, besides already published papers, more data are

necessary to demonstrate that resistance correlates with clinical failure.

Hernandez and Daniels Red., (1996) studied the nonulcerated;

uncomfortable oral mucosal lesions that are often thought to be caused by chronic

xerostomia develop in some patients with Sjdgren‘s syndrome. They found that these

lesions (1) clinically resemble chronic atrophic candidiasis, (2) usually yield Candida

species from their surface, and (3) can be eliminated by topical antifungal drugs in

spite of continuing xerostomia. In 246 patients who had primary or secondary

Sjdgren‘s syndrome, we correlated the presence or absence of atrophic oral mucosal

lesions with the patient‘s salivary function and other clinical features. The 91 patients

(37%) who had these lesions were older, had a greater frequency of primary SS and of

oral symptoms, had had oral symptoms for a longer period, had more salivary gland

inflammation, and had lower stimulated parotid flow rates than the 155 patients

without chronic atrophic candidiasis @ < 0.05.

Rusk-in et al., (1992) studied the effectiveness of clotrimazole troches and

nystatin suspension to prevent oral candidiasis in immunosuppressed orthotropic liver

transplant patients. Thirty-four patients received clotrimazole troches, 10 mg, five

times daily, or nystatin suspension, 500,000 units, four times daily. Prophylaxis was

initiated after exudation after transplantation and continued throughout the

hospitalization. One of 17 patients in each treatment group developed clinical and

microscopic evidence of an oropharyngeal Candida infection. This gave an intragroup

and an overall infection rate of 5.9%. They concluded that either nystatin or

clotrimazole may be used for candidiasis prophylaxis in orthotropic liver transplant

patients.

Sangeorzan et al., (1994) conducted a prospective observational study of 92

patients over 1 year, including a nonblinded, randomized treatment trial of thrush with

clotrimazole troches or oral fluconazole. Oral sites were cultured monthly and when

thrush occurred. C. albicans strains were typed by contour-clamped homogeneous

electric field electrophoresis. Modification in strains was evaluated over time and in

regard to their associations with particular sites, episodes of thrush, relapse after

treatment, and colonization of sexual partners. Susceptibility to fluconazole was tested

and contour-clamped homogeneous electric field analysis was done on these strains to

determine the epidemiology of fluconazole resistance.

Cuttner et al., (1986) recently reported their experience with clotrimazole in

prevention of oral candidiasis in patients with acute leukemia. They claimed this

agent was superior to nystatin, although the number of patients was very small and the

control group received placebo and no other prophylactic measures. In 1979, my

colleagues and I reported our experience.

Graybill et al., (1998) studied the relative efficacy of a new oral solution

formulation of itraconazole and fluconazole tablets in the treatment of OPC. OPC is

the most general opportunistic infection in individuals who are positive for the human

immunodeficiency virus (HIV) and those who have progressed to acquired

immunodeficiency syndrome. Anti fungal drug like Itraconazole has a broad in vitro

spectrum of activity, including a wide variety of Candida species.

Maheshwari et al., (2006) formulated the tetracycline-serratiopeptidase

containing periodontal gel formulation. They complete an endeavor to reduce polymer

concentration and to obtain reasonable viscosity at the less concentration of

poloxamer by addition of a viscosity modifier. Cold method was used to formulate gel

of pluronic in 20% w/w concentration. The outcome of the amount of tetracycline and

aerosil on gel properties was studied. Various parameters used for the evaluation of

gel were polarizing microscopy, gelation, gel melting, bioadhesion, viscosity, drug

release, and stability of enzyme. An in vivo study was performed to evaluate the

clinical efficiency of the liquid crystalline gel. A total of thirty subjects of both sexes

who were more than twenty one years old and had been diagnosed as suffering from

chronic localized or generalized periodontitis were considered for the study. Addition

of aerosil to the gel favored hexagonal phase formation. Viscosity and bioadhesive

increased with an increase in the concentration of aerosil. Drug Release of

tetracycline was prolonged as the concentration of aerosil increased. Various clinical

parameters confirmed the acceptability and efficiency of this gel system.

Eleni Pitsouni and Christos Iavazzo., (2007) aimed to compare the in vivo

and in vitro activity and the safety of per os itraconazole and fluconazole treatment of

uncomplicated acute vaginal/vulvovaginal candidiasis in nonpregnant women. They

used Pub Med, Scopus, Web of Science, and Cochrane Library to identify the studies

that were relevant to our meta analysis RCTs. Six RCTs were integrated in this study

that comprised 1092 enrolled patients with signs and symptoms of

vaginal/vulvovaginal candidiasis that was confirmed by microscopy and/or

microbiologic cultures that were obtained from the ectocervix and/or vaginal fundus.

They concluded that there was no difference between itraconazole and fluconazole

regarding clinical cure.

Albert Mansour., (1981) studied the eradication of indolent oral candidiasis

which is frequently difficult in infants with chronic mucocutaneous candidiasis or

severe combined immunodeficiency. The standard treatment is an oral nystatin

suspension. Invariably, most of the orally administered antifungal agent is swallowed

and inadequate contact with the oral mucosa is achieved. Other antifungal agents,

such as 5-fluorocytosine and amphotericin B, are available but their use is restricted

either by rapidly developing resistance or toxicity, He described a novel approach to

the administration of the antifungal agent‘s nystatin and clotrimazole.

Revankar et al., (1998) conducted a prospective, randomized study on

human immunodeficiency virus (HIV)-positive patients with CD4 cell count, 350 3

106/L and oropharyngeal candidiasis. Following initial treatment, 20 patients (16 of

whom completed 3 months of follow-up) received continuous fluconazole at 200

mg/day, and 48 patients (28 of who completed follow-up) received intermittent

therapy at the time of symptomatic relapses. Oral samples were collected weekly

during episodes of infection and quarterly as surveillance cultures. Advance of

resistance was defined as a fourfold rise in minimum inhibitory concentration (MIC)

to at least 16 mg/mL, from the initial culture in the same species, the emergence of

new, resistant (MIC $16 mg/mL) species, or a significant increase in the proportion of

resistant isolates.

Redding et al., (2004) investigated the oropharyngeal candidiasis (OPC) in

patients receiving radiation for head and neck cancer occurring in approximately 25%

of patients. C.albicans has been described as the primary infecting organism.

Currently, other organisms, particularly Candida glabrata, have emerged as causative

agents of OPC among immunocompromised patients. This revise describes the

characteristics of 6 patients with head and neck cancer treated with radiotherapy at

our institution, who were found to have Candida glabrata–associated OPC and their

responses to oral fluconazole. All 6 patients were successfully treated with oral

fluconazole. However, most did not respond to the usual dose of 100 mg/day

necessitating doses ranging from 200 to 800 mg/day to achieve clinical cure. All 3

patients receiving radiation only were successfully treated with up to 200 mg/day; 2

of 3 patients receiving concomitant chemoradiation required doses ranging from 400

to 800 mg/day.They concluded that as with systemic infection, previous fluconazole

use appears to be a risk factor for this infection, but not with all patients.

Carrillo-Munoz et al., (2002) investigated the in vitro susceptibility of 225

clinical isolates of yeasts to ciclopiroxolamine (CPO) and compared with that of

clotrimazole, econazole, ketoconazole, miconazole, tioconazole, fluconazole,

itraconazole and nystatin using a standardized agar diffusion method (NeoSensitabs).

Two hundred and eight strains of yeasts comprising 16 species of Candida and 22

strains belonging to other yeast genera were tested. One strain (0.4%) was resistant,

four strains (1.8%) of intermediate susceptibility and 220 strains (97.3%) susceptible

to CPO. More strains were susceptible to CPO than to the other antifungal studied.

Susceptibility patterns of antifungal agents were not linked to species. They found

that an in vitro antifungal susceptibility profile of CPO was better than topical azole

derivatives or fluconazole and itraconazole against a wide variety of clinically

important yeasts.

He X, et al., (2004) investigated the epidemiology of oral candidiasis which

is the most common fungal infection in patients with human immunodeficiency virus

(HIV) infection and the effect of the treatment of thrush in them. Ninety-two men

with HIV were experimental for a period of 1 year. They were examined, classified

according to type of HIV infection, had risk factors identified, and thrush history and

treatment history obtained. Oral sites were cultured at the commencement of the study

and then monthly, or when thrush occurred. Candida albican strains were typed by

contourclamped homogenous electric field (CHEP) electrophoresis. Changes in

strains were evaluated over time for association with particular anatomic sites,

episodes, relapse after treatment, and colonization of sexual partners. A non-blinded,

randomized comparison was made between treatment with clotrimazole troches and

oral flucanazole. Difference in outcome related to treatment and significance of risk

factors for development of thrush were analyzed by the chi-square test. The mean age

of the population was 38.5 + 0.9 years. Twenty-eight percent had acquired

immunodeficiency syndrome (AIDS), 31% had AIDS-related complex, and 41% were

as symptomatic. Yeast colonized in 84% of patients. C alb cans account for all

isolates. Nineteen different C albicans strains caused 82 episodes in 45 patients. They

accomplished that the clinical cure rates were similar between fluconizole (96%) and

clotrimizole (91%), but mycological cure was better with fluconizole (49%) than

clotrimizole (27%).

Meunier et al., (1994) reported on the value of antifungal prophylaxis with

antifungal drugs in preventing oropharyngeal candidiasis. Randomized trials

comparing non-AIDS immunocompromised patients receiving or not an oral

antifungal agent were reviewed. Colonisation of the throat with C. albicans is a risk

factor when cultures for this species of yeasts remain positive after commencement of

the prophylaxis. The results of the trials were meta-analyzed and we obtained a

combined probability ratio for developing oropharyngeal candidiasis of 0.15 when

under antifungal prophylaxis (confidence interval at 95%: 0.10422, x 2 statistics of

90.77, P< 0.0001). They concluded that there is a strong valuable effect of antifungal

prophylaxis against the incidence of oropharyngeal candidiasis.

Exner et al., (1985) developed a test for comparative investigation of

oropharyngeal antiseptics Studies in the urological and gynecological field were also

carried out. They chose cL-haemolytic streptococci to establish the effectiveness of

pharyngeal antiseptics, since these micro-organisms are the most abundant of the

normal aerobic flora in the mouth and are of major significance in the maintaining of

the normal flora. Since inflammation of the oropharyngeal cavity caused by Candida

albican is an important indication for the use of mucous membrane antiseptics as a

substitute to antimycotics, their efficiency against this organism was also assessed. In

preliminary studies they therefore required subjects with steadily high C. albicans

colonization of the oropharynx. They found appropriate pre-conditions in patients

with tumors of the oropharynx who had undergone radiation treatment. In almost two

thirds of these patients, C. albicans increased qualitatively and quantitatively by up to

103.

The following tests were made:

(1) A comparative investigation on the effectiveness of chlorhexidine and

PVP-I on hemolytic streptococci in the oropharyngeal cavity;

(2) A comparative investigation on the reduction of C. albicans and haemolytic

streptococci by irrigation with PVP-I or nystatin.

The use of cheap topical alternatives, e.g. oil of melaleuca (tea tree oil (TTO)),

chlorhexidine (CHX), povidone iodine (PI) and gentian violet (GV), to treat oral

candidiasis in human immunodeficiency virus (HIV)-infected patients has been

projected in resource-poor countries.

Traboulsi et al., (2008) conducted pre-clinical studies comparing the

antifungal activity of these agents which were lacking and compared the minimal

inhibitory concentrations (MICs) of TTO, GV, PI, CHX and fluconazole (FLZ)

against 91 clinical Candida strains using Clinical and Laboratory Standard Institute

(CLSI) methodology. Isolates were obtained from the oral cavity of acquired immune

deficiency syndrome (AIDS) patients. Between the topical agents examined, GV

showed the most potent activity against all Candida isolates tested (MIC range, MIC

for 50% of the organisms (MIC50) and MIC for 90% of the organisms (MIC90) of

0.03–0.25 g/mL, 0.06g/mL and 0.12 g/mL, respectively). CHX was 64 times less

active than GV (MIC range, MIC50 and MIC90 of 0.5–16g/mL, 4g/mL and 8g/mL,

respectively). The lowest antifungal activity was seen for PI (MIC90 =

0.25%).Additionally, GV, unlike the other topical agents tested, was fungicidal

(minimum fungicidal concentration = 1g/mL) against Candida albican isolates (n =

83). In addition, GV showed activity against FLZ-resistant C. albicans (n = 3). The

mixture of GV and FLZ was not antagonistic and there was no interface between the

two compounds. GV possesses potent antifungal activity against FLZ-susceptible and

resistant Candida strains and is not antagonistic when used in combination with FLZ.

Yanai et al., (2006) evaluated the disinfectant properties and safety of

Povidone iodine which possesses broad-spectrum antimicrobial activity and used

clinically as a disinfectant as a contact lens solution. The concentrations of Povidone

iodine required reducing the number of Staphylococcus aureus or Candida albican by

3 log units were lower than were those of hydrogen peroxide, polyhexamethylene

biguanide, and benzalkonium chloride. The cytotoxicity of Povidone iodine for

cultured human corneal epithelial cells was less than that of the other three agents.

They accomplished that the safety margin for Povidone iodine was best among the

tested compounds and suited for use as a contact lens disinfectant.

Altonen., (1976) studied the two degerming mouth rinses, 1% povidone

iodine and a 0.2% aqueous solution of chlorhexidine gluconate with regard to their

degerming effect on the saliva. The study comprises two parts. In the first part 19

dental students with good oral hygiene rinsed their mouths at weekly intervals with 10

ml of the PVP-I and 10 ml of the CHX solution. A control group of 12 students and

nurses with healthy teeth and gums rinsed their mouths with 10 ml of plain water. In

the second part 11 adult patients with periodontal disease used the two test rinses at

weekly intervals both before and after periodontal prophylaxis including scaling of

the teeth .Non-stimulated saliva was sampled immediately before and 5, 30, 60, and

120 rain after each rinse.

Ameye et al., (2005) studied the spray-dried Amioca® starch/Carbopol®

974P mixtures and were evaluated as potential buccal bioadhesive tablets. Carbopol®

(C 974P) concentrations from 5 to 75% were tested. All spray-dried mixtures showed

an equivalent or better bioadhesive capacity compared to a reference formulation

(DDWM/C 974P 95/5). The bioadhesive capacities of Amioca®/Carbopol® 974P

mixtures were improved by spray-drying. All spray-dried mixtures showed

considerably higher work of adhesion values compared to their equivalent physical

mixtures. The effect of Carbopol® concentration on the in vivo adhesion time of

placebo tablets and in vitro miconazole nitrate release was tested. The ratio

Amioca®/C 974P 70/30 showed the longest in vivo adhesion time (24.5±8.5 h).

Lower and higher C 974P concentrations had a shorter in vivo adhesion time. The

mixture containing between 15 and 30% C 974P could all sustain the in vitro

miconazole nitrate release over 20h. Again, lower and higher C 974P concentrations

showed a faster in vitro miconazole release. The drug loading capacity of a spray-

dried mixture containing 20% C 974P was investigated in vivo in dogs using

testosterone as model drug. They concluded that the spray-dried mixture could be

loaded with 60% drug without losing its in vivo bioadhesive and pharmacokinetic

properties.

chun et al., (2003) deliberate a system of polymeric film composed of

Carpool, Pluronic and hydroxypropyl methylcellulose and studied the effects of

composition of the film on adhesion time, swelling ratio, and dissolution of the film

were studied. The effects of plasticizers or penetration enhancers on the release of

triamcinolone acetonide (TAA) were also studied. The hydrogen bonding between

Carbopol and Pluronic played important role in reducing swelling ratio and

dissolution rate of polymer film and increasing adhesion time. The swelling ratio of

the composite film was significantly reduced and the adhesion time was increased

when compared with Carbopol film. As the ratio of Pluronic to HPMC increased from

0/66 to 33/33, the release rate of triamcinolone acetonide decreased. However, no

further significant reduce in release rate was observed beyond the ratio of 33/33. The

release rate of triamcinolone acetonide in the polymeric film containing polyethylene

glycol 400, a plasticizer, showed the highest release rate followed by triethyl citrate,

and castor oil. The release rate of triamcinolone acetonide from the polymeric film

containing penetration enhancers was slower than that from the control without

enhancers. They found that a preparation of a buccal patch is feasible with the

polymeric film composed of Cabopol, Pluronic and hydropropyl methylcellulose.

Perioli et al., (2004) investigate the muco adhesive tablets using different

mixture of cellulose and polyacrylic derivative in order to obtain new formulations

containing metronidazole for periodontal disease treatment. All tablets were

characterized by swelling studies, ex vivo and in vivo mucoadhesive time, ex vivo

mucoadhesion force, in vitro and in vivo release. They found that the best

mucoadhesive performance and the best in vitro drug release profile were achieved by

using hydroxyethyl cellulose (HEC) and carbomer 940 2:2 ratios. The selected tablet,

containing 20 mg of metronidazole, performed 12 h drug sustained release with

buccal concentration always higher than its MIC.

Miyazaki et al., (1998) developed oral mucosal bioadhesive tablets of

diltiazem by directly compress the drug with a mixture of chitosan and sodium

alginate. In vitro adhesion studies indicated adhesion properties similar to those of a

commercial formulation. In vitro release of diltiazem was fast and could be modified

by changing the mixing ratio of chitosan and sodium alginate; increasing the chitosan

content in the tablets and/or the viscosity grade of the alginate resulted in a decrease

in the in vitro release rate. They concluded that the bioavailability of diltiazem was

69.6% from tablets with a 1:4 chitosan/alginate weight ratio when administered

sublingually to rabbits compared with 30.4% by oral administration.

Khanna et al., (1996) evaluate the buccoadhesive erodible tablets for local

release of (CLT) to the oral cavity using different bio-adhesive polymers along with

soluble excipients like mannitol and PEG-6000. An equipment simulating the in vivo

conditions of the mouth was designed in order to assess in vitro, the bio-adhesive

occurrence and release characteristics of these tablets. The in vitro adhesion time and

release individuality were found to be a function of the type of polymer and also the

total composition of the tablets.

Vishnu Patel., (2007) developed mucoadhesive buccal devices of propranolol

hydrochloride (PRH) in the forms of bilayered and multilayered tablets. The tablets

were formulated using (SCMC) and (CP 934) as bioadhesive polymers to disclose

mucoadhesion and ethyl cellulose (EC) to act as an impermeable backing layer. As

compared with bilayered tablets, multilayered tablets showed slow release rate of drug

with enhanced ex vivo bioadhesive strength and superior ex vivo mucoadhesion time.

The mechanism of drug release was found to be non-Fickian diffusion (value of n

between 0.5 and 1.0) for both the buccal devices. The constancy of drug in both the

optimized buccal devices was tested for 6 hours in natural human saliva; both the

buccal devices were found to be established in natural human saliva.

Qi et al., (2007) discussed on the problems of regular ophthalmic solutions

often eliminate rapidly after administration and cannot provide and maintain an

adequate application of the drug in the precorneal area. To solve these problems, they

developed a thermosensitive in situ gelling and mucoadhesive ophthalmic drug

release system containing puerarin based on poloxamer analogs (21% (w/v)

poloxamer 407/5% (w/v) poloxamer 188) and carbopol (0.1% (w/v) or 0.2% (w/v)

carbopol 1342P NF). The combined solutions would transfer to firm gels under

physiological condition and attach to the ocular mucosal surface for a relative long

time. The incorporation of carbopol 1342P NF not only did not affect the

pseudoplastic behavior with hysteresis of the poloxamer analogs solution and leaded

to a higher shear stress at each shear rate, but also improved the mucoadhesive force

significantly. In vitro release studies established diffusion-controlled release of

puerarin from the combined solutions over a period of 8 h.

Odds., (1993) discussed that itraconazole which is a triazole-derivative

antifungal agent with a particularly broad spectrum of action in vitro, in experimental

animals in vivo and in clinical trials when taken orally, achieve high and sustained

levels of active drug in many tissues, including skin, Nail and most deep organs. Its

clinical value has been attest in all forms of mycosis affecting the skin and mucous

membranes and in onychomycosis. In systemic infections, clinical trials have lead to

recommendation that itraconazole is the current drug of choice for blastomycosis,

histoplasmosis, paracoccidioidomycosis, lymphocutaneous sporotrichosis. Chronic

dispersed aspergillosis and many cases of phaeohyphomycosis. It is also finding

application in deep-seated Candida infections and in cryptococcosis. Its safety profile

is extremely superior, with very few non-trivial adverse experience noted in a large

series of patients treated and monitored. Itraconazole therefore represents a useful

therapeutic advance for the management of most forms of fungal infection.

Epsthn and Polsky., (1998) discussed about oropharyngeal candidiasis which

is more common with the increased use of antibiotics and immunosuppressive agents.

This infection is also connected with such advances in medical management as

chemotherapy and organ transplantation and with human immunodeficiency virus

infection. Different topical and systemic agents are available to treat patients with

candidiasis, but optimal management can be elusive. Management of uncomplicated

oropharyngeal candidiasis in the immunocompetent patient involve select a particular

formulation of a topical medication base on oral conditions, length of contact time,

and taste, texture, and cost of the medication. Management of severe oropharyngeal

candidiasis, particularly in patients with a compromised immune system, is often

more complex and relapse are common. Reports of resistance to systemic agents,

predominantly in patients needing recurrent therapy, are increasing. Amphotericin B,

long used as an intravenous agent, is now available as an oral suspension that may

offer therapeutic benefits equivalent to therapy without the toxicity associated with

systemic absorption.

Le Conte et al., (1994) investigated the killing curves for both free and

liposomal itraconazole against Candida albican. The in vivo effectiveness of both

itraconazole formulations was assessed in a murine model of systemic candidiasis.

They found that there was no fungicidal effect in vitro, and the in vitro time-kill

curves were not prognostic of the in vivo efficacy of both formulations of

itraconazole. They also found that in vivo, treated mice survived longer than the

control mice, but there were no major differences between the two treated groups.

Murray et al., (1997) studied the efficacy and safety of itraconazole oral

solution (200 mg once daily) and CT troches (10 mg five times daily) in a population

of immune compromised subjects composed primarily of patients with human

immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS).

Patients were treated for 14 days; patients who exhibited a clinical response were

followed up for an additional month to document the occurrence of relapse. Efficacy

was judged by changes from baseline in symptoms of oropharyngeal candidiasis

(erythema, soreness/burning), extent of oral lesions, and the presence/absence of

Candida species on fungal culture. A total of 162 patients were randomized, and 149

were evaluated for efficacy. The percentage of patients with negative cultures at the

end of treatment was significantly greater in the itraconazole group than in the

clotrimazole group (60% vs. 32%, respectively).

Shastri and Patel., (2010) studied that the continued and prolonged drug

delivery approaches are very common in today‘s Pharmaceutical formulation design

and research work is still going on in achieving better drug invention. Ophthalmic use

of viscosity-enhancing agents, penetration enhancers, cyclodextrin, prodrug

approaches, and ocular inserts and the ready existing drug carrier systems along with

their concentration to ophthalmic drug delivery are very common to improve ocular

bioavailability Among these hydrogel (in situ gel forming) systems are of very

important. They help to increase in precorneal residence time of drug to an enough

extent that an ocular delivered drug can exhibit its maximum biological action. The

concept of this innovative ophthalmic delivery method is to decrease the systemic side

effects and to create a more pronounced effect with lower doses of the drug. Many

polymers are very valuable with majority of hydrogels, which undergo reversible sol-

gel phase transition in the ocular cul-de-sac to form viscoelastic gels due to phase

changes of polymers in response to the physiological environment (temperature, pH

and presence of ions in organism fluids. These in situ forming gels can be applied as

solution and exhibit pseudo plastic behavior to diminish obstacle with blinking,

increase pre corneal residence of the delivery system and enhanced ocular

bioavailability. Now a day‘s in situ gels have been used as vehicle for the delivery of

drugs for both local treatment and systemic effects. Different administration routes

other than ocular have been explored, including for example, cutaneous and

subcutaneous delivery, dental, buccal delivery and delivery to the esophagus,

stomach, colon, rectum and vagina.

Gupta, Singh., (2008) investigated a pH mediated in situ gelling system using

prilocaine for periodontal anesthesia using combination of chitosan ad hydroxyl

propyl methylcellulose. The gel so developed can be used as anesthetic in lengthy

dental surgery. The gel was evaluate for many parameters like gelation PH, viscosity,

physiochemical properties, In vitro release, sterility and stability.gel with chitosan

(0.25%w/v) and HPMC (0.25%) was establish to have good gelatin near ph 7.4 (PH of

mucous) with prolong action.

Bochot A., (1998) intended at providing an ophthalmic delivery system based

on the dispersion of liposomes into a thermosensitive gel made of a copolymer of

ethylene oxide and propylene oxide (Pluronic 407). At high concentration of 20-30%

and temperature of about 20°C, Pluronic 407 passes from a solution to a gel. In place

of stabilization of liposomes in the gel, PEG2000-DSPE was introduced in their

composition. Adsorption studies investigated by size and ζ-potential measurements

have exposed that the adsorption was higher for positively charged or neutral non-

sterically stabilized liposomes. Pluronic 407 adsorbed to a lower extent with

negatively charged or PEG-DSPE containing liposomes. Moreover using a fluorescent

aqueous marker, it was shown that liposome permeability was dramatically reduced in

the presence of Pluronic 407 when PEG-DSPE was incorporated into the liposomes.

This data suggests that Pluronic 407 could adsorb, at different extents, to all types of

vesicles but that bilayer destabilization by the copolymer was reduced when

liposomes were sterically stabilized. This was explains by the poor accessibility of the

Pluronic to the phospholipidic which is the possible consequence of the steric

repulsion effect induced by polyethylene glycol. Finally, it was shown that the

thermosensitivity of Pluronic 407 was maintained after introducing the liposomes into

the gel.

Aditya Gupta., (2001) reported that onychomycosis is a chronic fungal

infection of the nails. When onychomycosis is caused by dermatophytes, that is

Trichophyton, Epidermophyton, or Microsporum sp.

Zhou and Donovan., (2001) designed a system used putative bioadhesive

polymers such as methylcellulose, SCMC, HPMC, CP 934P, chitosan glutamate and

poloxamer F127 for the study of mucociliary clearance with the use of rat model. The

mucociliary clearance for these polymer gels from nasal cavity was determined by

following removal of microspheres which are fluorescently labeled and incorporated

in the formulation. It was found that the poloxamer F127 and other polymer gel

formulations have longer residence times and hence decrease mucociliary clearance.

Charrueau et al., (2001) evaluated the use of Pluronic 407 for rectal

administration of short chain fatty acids. Five thermogels were prepared with Pluronic

407 at concentrations ranging from 17% to 20% and viscosities were precise at room

temperature and 37°C, and their gelling temperatures were determined. From the

threshold concentration of 17.5%, the solutions show sign of Newtonian character at

room temperature (50-80 mPa.s), gelled at 37°C.The higher the concentration & the

higher the viscosity (1750 to 49,000 mPa.s), the lower the gelling temperature (27.6°C

to 23.4°C), and the stronger the work of adhesion (2.2 to 4.5 mJ). Short chain fatty

acid release from the 18% polymer gel was decreased by 60% compared to the rectal

solution. The 18% Pluronic 407 concentration provided a solution that was liquid at

room temperature that gelled at 37°C, possessed adhesive properties, and controlled

short-chain fatty acid release.

Pisal, Reddy., (2004) designed a thermoreversible pluronic gel system for

nasal administration of Melatonin for use in case of sleep disorders. With the use of

cold method, aqueous poloxamer gels containing drug (0.5 mg/0.1ml), PEG 400 and

PEG 15000 were studied for gelation and gel melting. Melatonin shifted gelation

range to higher temperature while PEG narrowed the gel range. It was observed that

increase in poloxamer concentration, flux of diffusion decreased. Bimodal pattern was

observed with pluronic gel (20%w/w, 1mg/0.1 ml) showing a desired peak flux

(0.248µg/min./cm2) at 300min. Nasal cavity gels prepared show fast onset of action

and induced sleep within fifteen minutes. They proved that melatonin gels can be used

in the treatment of circadian cycle sleep disorders.

Majithiya et al., (2006) investigated a thermoreversible mucoadhesive gel

formulation for intranasal delivery of sumatriptan using thermoreversible polymer

poloxamer F127 and mucoadhesive polymer carbopol 934P. preparation were

developed so as to have gelation temperature below 34°C so that gelation will be at

physiological temperature after intranasal administration. Physical appearance and

viscosity measurement were used for determination of gelation temperature. Gelatin

temperature of formulations decreases as the deliberation of carbopol increases (that

is from 29°C for 18% poloxamer F127 to 23.9°C for poloxamer F127, 0.5%

carbopol). Bioadhesive force in terms of detachment stress, determined using sheep

mucosal membrane was found to increase with increasing concentration of carbopol.

From the results of in vitro drug penetration studies, it was clear that effective

permeation coefficient could be significantly increased by using in situ gelling

formulation having concentration of carbopol 0.3% or greater. Also the

histopathological examination did not detect any damage during in vitro permeation

studies. It was concluded that in situ gelling and mucoadhesive nasal formulation of

sumatriptan prepared from poloxamer F127 represents competent way for

prolongation of nasal residence and nasal absorption.

Lai LIU, Dongkai., (2005) designed a thermosensitive nasal gel system of

dextromethorphan hydrobromide and also in vitro drug release studies. The thermo

induced polymer used for the preparation of nasal drop was Pluronic 407. Vertical

diffusion cell was used for in vitro drug release study. The Pluronic solution of 20%

w/w concentration and 2.5% w/w PEG 6000 is liquid at room temperature, and then

undergoes a phase transition to a semisolid gel when being heated up to 33°C.

Higuchi equation kinetics(r>0.99) is followed by drug release form Pluronic vehicle.

This formulation thus prove to be efficient than traditional nasal preparations.

Gonjari and Kasture., (2007) designed a nasal controlled release formulation

of a model drug propranolol hydrochloride restricted within liposomes separate in a

thermoreversible gel by using polymer like poloxamer 407 and combination of

poloxamer 407 with bioadhesive polymer like carbopol 934P. Liposomes were

formulated by reverse phase evaporation method using soya lecithin and cholesterol

in different ratios. The combination of soya lecithin and cholesterol showing

maximum percentage setup was used for further spreading into gel prepared by using

thermoreversible polymer and thermoreversible gel containing a mucoadhesive. The

results show that gel is having capacity to accommodate the liposomes without losing

its gelation property. Also formulation showed a satisfactory result. It was found that

this formulation is supposed to be useful in prolonging the nasal residence time of the

encapsulated drug, in controlling its release and subsequently improving nasal

bioavailability.

El Hady., (2003) proposed that mebeverine hydrochloride (MbHCl) suffers

from extensive first pass effect and the bioavailability of it can be superior and its

absorption can be restricted to lower rectum only by using rectal solution having

gelation temperature range of 30-37 C. Mixtures of Pluronic 407 and Pluronic 188

were used for the temperature sensitive gelation property. The cold method was used

for the preparation of rectal solutions. Hydroxypropyl methyl cellulose (HPMC),

hydroxyethyl cellulose (HEC), methyl cellulose (MC) and polyvinylpyrrolidone K-25

(PVP K-25) were used to modulate gel strength and to impart bioadhesive force to

MbHCl-poloxamer rectal solution. Addition of 10% MbHCl in rectal solution was

found to increase gelation temperature of Pluronic mixtures while the effect was

reversed upon the addition of bioadhesive polymers. On the other hand, these

polymers resistant the gel strength and the bioadhesive force of the prepared

solutions. The effect was most pronounced with MC. As the concentration of

cellulosic mucoadhesive polymers enhanced, the release of MbHCl was retard to the

different extents and it was possible to prolong drug release over a period of 8 hrs.

Order of polymers according to their release retarding effect was found to be MC >

HPMC > HEC. They found that PVP K-25 had no effect on the drug release.

Pretreatment of guinea pigs with MbHCl rectal solution [Pluronic r 407/ Pluronic 188/

MC/ MbHCl (23/ 7/ 1.5/ 10% w/w)], having satisfactory gel strength, mucoadhesive

properties and acceptable sustained release profile with zero order release kinetics,

showed a significant extended spasmolytic effect to spasmogens-induced contractions

on guinea pig ileum and did not cause any histological damage to the rectal tissues.

Yong et al., (1999) prepared a series of ibuprofen loaded liquid suppository

using eutectic mixture with menthol, and investigated the effects of menthol and

poloxamer 188 (P188) on the aqueous solubility of ibuprofen. The physicochemical

properties such as gelation temperature, gel strength and bioadhesive force of various

formulations composed of ibuprofen, menthol and poloxamer 188 were investigated.

The pharmacokinetic study of ibuprofen delivered by the liquid suppositories

composed of poloxamer 188 and menthol were then performed. The solubility of

ibuprofen increased in absence of poloxamer 188 until the ratio of menthol to

ibuprofen increased from 0:10 to 4:6 followed by an abrupt decrease in solubility

above the ratio of 4:6. This indicated that four parts of ibuprofen formed eutectic

mixture with six parts of menthol. The solutions with the same ratio showed sudden

increase in solubility in presence of poloxamer 188.Besides the solution with ratio of

4:6 showed more than 2.5- and 6-fold increase in the solubility of ibuprofen compared

with that without additives and that without menthol, respectively.The poloxamer gel

with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the

maximum solubility of ibuprofen, 1.2 mg/ml. It was found that ibuprofen increases

gelation temperature whereas weakened the gel strength and bioadhesive force of

liquid suppositories. However menthol shows reverse behavior due to formation of

eutectic mixture with ibuprofen. The ibuprofen-loaded liquid suppositories [P

188/menthol/ibuprofen (15/0.25/2.5%)] with the maximum ibuprofen solubility of 1.2

mg/ml were administered easily to the anus and remain at the administered site

without leakage after the dose. Higher initial plasma concentrations, Cmax and area

under curve were observed than that of solid suppository that indicates the drug from

poloxamer gel could be more absorbed than that from solid one in rats. They

concluded that the liquid suppository system with P 188 and menthol serves to be

more effective and convenient dosage form for rectal administration and will be

expected to enhance the rectal bioavailability of ibuprofen.

Lee et al., (2004) prepared the formulation for the local delivery of

vancomycin with the use of pluronic F127 for the effective treatment of otitis media

caused by methicillin resistant Staphylococcus aureus (MRSA).The phase transition

property of pluronic F127, which is liquid at room temperature and becomes solid at

body temperature, made injection convenient and hence reduced the side effects of the

potent antibiotic. The temperature responsive polymer–vancomycin matrix system

was also shown to effectively deliver vancomycin locally to the infected inner ear,

plus the MRSA growth was inhibited by the formulation. From in vivo studies it was

clear that otitis media was cured from sustained local delivery of vancomycin. They

found that the system has potential clinical application for treating chronic otitis

media with improved patient compliance and better therapeutic efficacy.

Yuthika. Samaranayake., (2001) they reviewed the extensive literature on

animal experiments mainly appertaining to the host predisposing factors that initiate

and perpetuate these infections. The monkey, rat, and mouse are the choice models for

investigating oral candidiasis, but comparisons between the same or different models

appear difficult, because of variables such as the study design, the number of animals

used, their diet, the differences in Candida strains, and the duration

of the studies.

These variables notwithstanding, the following could be concluded. The ape model is

ideal for investigating Candida-associated denture stomatitis since both erythematous

and pseudomembranous lesions have been produced in monkeys with prosthetic

plates; they are, however, expensive and difficult to obtain and maintain. (ii) The rat

model (both Sprague-Dawley and Wistar) is well proven for observing chronic oral

candidal colonization and infection, due to the ease of breeding and handling

and their

ready availability. (iii) Mice are similar, but in addition there are well characterized

variants simulating immunologic and genetic abnormalities (e.g., athymic, euthymic,

murine-acquired

immune deficiency syndrome, and severe combined

immunodeficient models) and hence are used for short-term studies relating the

host

immune response and oral candidiasis. Nonetheless, an ideal, relatively inexpensive

model representative of the human oral environment in ecological and microbiological

terms is yet to be described. Until such a model is developed, researchers should

pay

attention to standardization of the experimental protocols described here to obtain

broadly equal and meaningful data.