in situ gel: application and uses of polymers · system that are instilled as drops into eye &...

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Nikode et al. World Journal of Pharmacy and Pharmaceutical Sciences

IN SITU GEL: APPLICATION AND USES OF POLYMERS

Snehal Nikode*, Gauri Dixit and Kanchan Upadhya

Department of Pharmaceutics, Priyadarshini J L College of Pharmacy, Hingna Road,

Nagpur, Maharashtra, India.

ABSTRACT

The development of in situ gel system has received considerable

attention over the past few years. This interest has been sparked by

advantages shown by in situ forming delivery system such as ease of

administration and reduced frequency of administration, improved

patient compliance and comfort. The formation of gels 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. Various biodegradable polymers that are used

for the formation of in situ gels include pectin, guar gum, carbopol,

Xyloglucan, gellan gum, alginic acid, Xanthum gum, Chitosan,

HPMC, Poloxamer etc. Mainly in situ gel administered by oral ocular,

rectal, vaginal, injectable and intaperitoneal routes. This review

presents a brief introduction to in situ gels, various approaches for in situ gelling system,

different types of polymers used and evaluation of in situ gelling system.

KEYWORDS: In situ gel, biodegradable polymer, pH sensitive, temperature sensitive.

INTRODUCTION

The development of in situ gel systems has received considerable attention over the past few

years. This interest has been sparked by the advantages shown by in situ forming polymeric

delivery systems such as ease of administration and reduced frequency of administration,

improved patient compliance and comfort.[1]

In situ gelling systems are liquid at room

temperature but undergo gelation when in contact with body fluids or change in pH. In

contrast to very strong gels, they can be easily applied in liquid form to the site of drug

absorption. At the site of drug absorption they swell to form a strong gel that is capable of

prolonging the residence time of the active substance. Both natural and synthetic polymers

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.041

Volume 5, Issue 7, 1638-1658 Review Article ISSN 2278 – 4357

*Corresponding Author

Snehal Nikode

Department of

Pharmaceutics,

Priyadarshini J L College

of Pharmacy, Hingna

Road, Nagpur,

Maharashtra, India.

Article Received on

19 May 2016,

Revised on 09 June 2016,

Accepted on 29 June 2016

DOI: 10.20959/wjpps20167-7212


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can be used for the production of in situ gels. In situ gel formation occurs due to one or

combination of different stimuli like pH change, temperature modulation and ionic cross-

linking. So, in situ gels are administered by oral, ocular, rectal, vaginal, injectable and intra-

peritoneal routes.[2,3,4]

Recent advances in in situ gels have made it possible to exploit the changes in physiological

uniqueness in different regions of the GI tract for the improved drug absorption as well as

patient’s convenience and compliance. In the current niche of drug delivery technologies, in

situ gels have made an irreplaceable space because of their unique characteristics. This

review presents a brief introduction to in situ gels, various approaches for in situ gelling

system, different types of polymers used and evaluation of in situ gelling system.[4,5]

IMPORTANCE OF IN SITU GELLING SYSTEM[6]

The major importance is the possibilities of administrating accurate & reproducible

quantities compared to already formed gel.

In-situ forming polymeric delivery system such as ease of administration & reduced

frequency of administration improved patient compliance & comfort.

Poor bioavailability & therapeutic response exhibited by conventional ophthalmic

solution due to rapid precorneal elimination of drug may be overcome by use of gel

system that are instilled as drops into eye & undergoes a sol-gel transition from instilled

dose.

Liquid dosage form that can sustain drug release & remain in contact with cornea of eye

for extended period of time is ideal.

Reduced systemic absorption of drug drained through the nasolacrimal duct may result in

some undesirable side effects.

ADVANTAGES[7,8,9]

Ease of administration, comfort

Reduced frequency of administration further

Improved patient compliance

Can be administered to unconscious patients

Drug gets released in a sustained and controlled manner

Natural polymers have inherent properties of biocompatibility, biodegradability, and

biologically recognizable moieties that support cellular activities.


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Synthetic polymers usually have well-defined structures that can be modified to yield

tailorable degradability and functionality.

In situ gels can also be engineered to exhibit bioadhesiveness to facilitate drug targeting,

especially through mucus membranes, for non-invasive drug administration.

In situ gels offer an important “stealth” characteristic in vivo, owing to their

hydrophilicity which increases the in vivo circulation time of the delivery device by

evading the host immune response and decreasing phagocytic activities.

DISADVANTAGES[10,11]

It is more susceptible to stability problems due to chemical degradation.

It requires high level of fluids.

It leads to degradation due to storage problems.

LIMITATIONS[12,13]

The quantity and homogeneity of drug loading into hydrogels may be limited, particularly

for hydrophobic drugs. Only drugs with small dose requirement can be given.

Lower mechanical strength, may result into premature dissolution or flow away of the

hydrogel from a targeted local site.

The high water content and large pore size of most hydrogels often result in relatively

rapid drug release.

Ease of application is questionable sometimes as some hydrogels are not sufficiently

deformable, thus injectable route may not be possible.

Eating and drinking may become restricted up to few hours.

IDEAL CHARACTERISTICS OF POLYMERS FOR PREPARATION OF IN SITU

GEL[14,15]

It should be compatible.

It is capable of adhering to the mucus membrane.

Preferred pseudo plastic behavior of polymer.

Good tolerance and optical clarity is more preferred.

It should influence the tear behavior.

The polymer should be capable of decreasing the viscosity with increasing share rate.


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MECHANISM OF IN SITU GEL

In situ formation based on physical mechanism

Swelling

In situ formation may also occur when material absorbs water from surrounding environment

and expand to desired space. One such substance is myverol (glycerol mono-oleate), which is

polar lipid that swells in water to form lyotropic liquid crystalline phase structures. It has

some bioadhesive properties and can be degraded in vivo by enzymatic action.[16]

Diffusion

This method involves the diffusion of solvent from polymer solution into surrounding tissue

and results in precipitation or solidification of polymer matrix. N-methyl pyrrolidone (NMP)

has been shown to be useful solvent for such system.[17]

In situ formation based on chemical reactions mechanism

Chemical reactions that results in situ gelation may involve precipitation of inorganic solids

from supersaturated ionic solutions, enzymatic processes, and photo-initiated processes.

Ionic crosslinking

Polymers may undergo phase transition in presence of various ions. Some of the

polysaccharides fall into the class of ion-sensitive ones. While k-carrageenan forms rigid,

brittle gels in reply of small amount of K+, i-carrageenan forms elastic gels mainly in the

presence of Ca2+

. Gellan gum commercially available as Gelrite is an anionic polysaccharide

that undergoes in situ gelling in the presence of mono- and divalent cations, including Ca2+

,

Mg2+

, K+ and Na

+. Gelation of the low methoxypectins can be caused by divalent cations,

especially Ca2+

. Likewise, alginic acid undergoes gelation in presence of divalent/polyvalent

cations e.g. Ca2+

due to the interaction with glucoronic acid block in alginate chains.[18]

Enzymatic cross-linking

In situ formation catalysed by natural enzymes has not been investigated widely but seems to

have some advantages over chemical and photochemical approaches. For example, an

enzymatic process operates efficiently under physiologic conditions without need for

potentially harmful chemicals such as monomers and initiators. Intelligent stimuli-responsive

delivery systems using hydrogels that can release insulin have been investigated. Cationic

pH-sensitive polymers containing immobilized insulin and glucose oxidase can swell in

response to blood glucose level releasing the entrapped insulin in a pulsatile fashion.


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Adjusting the amount of enzyme also provides a convenient mechanism for controlling the

rate of gel formation, which allows the mixtures to be injected before gel formation.[19]

Photo-polymerisation

Photo-polymerisation is commonly used for in situ formation of biomaterials. A solution of

monomers or reactive macromer and initiator can be injected into a tissues site and the

application of electromagnetic radiation used to form gel. Acrylate or similar monomers and

macromers because they rapidly undergo photo-polymerisation in the presence of suitable

photoinitiator. Typically long wavelength ultraviolet and visible wavelengths are used. Short

wavelength ultraviolet is not used often because it has limited penetration of tissue and

biologically harmful. A ketone, such as 2,2 dimethoxy-2-phenyl acetophenone, is often used

as the initiator for ultraviolet photo- polymerization, where as camphorquinone and ethyl

eosin initiators are often used in visible light systems. These systems can be designed readily

to be degraded by chemical or enzymatic processes or can be designed for long term

persistence in vivo. Photopolymerizable systems when introduced to the desired site via

injection gel. Photocured in situ with the help of fiber optic cables and then release the drug

for prolonged period of time. The photo-reactions provide rapid polymerization rates at

physiological temperature. Furthermore, the systems are easily placed in complex shaped

volumes leading to an implant formation.[21]

VARIOUS APPROACHES OF IN SITU GELATION

PH triggered in situ gelation

All the pH-sensitive polymers contain pendant acidic or basic groups that either accept or

release protons in response to changes in environmental pH. The polymers with a large

number of ionizable groups are known as polyelectrolytes. Swelling of hydrogel increases as

the external pH increases in the case of weakly acidic (anionic) groups, but decreases if

polymer contains weakly basic (cationic) groups. The most of anionic pH-sensitive polymers

are based on PAA (Carbopol, carbomer) or its derivatives. Likewise polyvinyl

acetaldiethylaminoacetate (AEA) solutions with a low viscosity at pH 4 form hydrogel at

neutral pH condition. Drug formulated in liquid solutions have several limitations, including

limited bioavailability and propensity to be easily removed by tear fluid. Kumar and

Himmelstein sought to minimize this factors and maximize this drug delivery by making a

poly (acrylic acid) (PAA) solution that would be gel at pH 7.4. The author found that at

concentrations high enough to cause gelation, however, the low pH of PAA solution would


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cause damage to surface of eye before being neutralized by the lacrimal fluid. This problem

was solved by partially by combining PAA with HPMC, a viscous enhancing polymer, which

resulted in pH responsive polymer mixtures that was solat pH 4 and gel at pH 7.4. Mixtures

of poly(methacrylicacid) (PMA) and poly (ethylene glycol) ( PEG) also has been used as a

pH sensitive system to achieve gelation.[22]

Fig 1: Mechanism of pH triggered in situ gel system.

Temperature triggered in situ gel

Temperature is the most widely used stimulus in environmentally responsive polymer

systems. The change of temperature is not only relatively easy to control, but also easily

applicable both in vitro and in vivo. In this system, gelling of the solution is triggered by

change in temperature, thus sustaining the drug release. These hydrogels are liquid at room

temperature (20–25°C) and undergo gelation when in contact with body fluids (35– 37°C),

due to an increase in temperature. The use of biomaterial whose transitions from sol-gel is

triggered by increase in temperature is an attractive way to approach in situ formation. The

polymers which show temperature induced gelation are Poloxamer or pluronics, cellulose

derivatives (methyl cellulose, HPMC, ethyl (hydroxyl ethyl) cellulose (EHEC) and

xyloglucan etc.[23]

Fig 2: Mechanism of temperature sensitive system

Ion activated in situ gelation

In this method, gelling of the solution instilled is triggered by change in the ionic strength. It

is assumed that the rate of gelation depend on the osmotic gradient across the surface of the


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gel. The aqueous polymer solution forms a clear gel in the presence of the mono or divalent

cations typically found in the tear fluids. The electrolyte of the tear fluid and especially Na+,

Ca2+ and Mg2+ cations are particularly suited to initiate gelation of the polymer when

instilled as a liquid solution in the conjunctival cul-de-sac. The polymer which shows

osmotically induced gelation is Gelrite or Gellan gum, Hyaluronic acid and Alginates etc.[24]

Fig 3: Mechanism of temperature sensitive system.

Polymers used as in situ gelling agents

Many natural, biodegradable, biocompatible and synthetic polymers are used in the

preparation of in situ gelling system.

Pectin

Fig 4: Structure of pectin

Properties

Pectins are a family of polysaccharides, in which the polymer backbone mainly comprises α-

(1-4)-D galacturonic acid residues. Low methoxy pectins (degree of esterification <50%)

readily form gels in aqueous solution in the presence of free calcium ions, which crosslink the

galacturonic acid chains in a manner described by egg-box model . Although the gelation of

pectin will occur in the presence of H+

ions, a source of divalent ions, generally calcium ions

is required to produce the gels that are suitable as vehicles for drug delivery. The main

advantage of using pectin for these formulations is that it is water soluble, so organic solvents

are not necessary in the formulation. Divalent cations present in the stomach, carry out the

transition of pectin to gel state when it is administered orally. Calcium ions in the complexed

form may be included in the formulation for the induction of pectin gelation.[25]


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Mechanism

Sodium citrate may be added to the pectin solution to form a complex with most of calcium

ions added in the formulation. By this means, the formulation may be maintained in a fluid

state (sol), until the breakdown of the complex in the acidic environment of the stomach,

where release of calcium ions causes gelation to occur. The quantities of calcium and citrate

ions may be optimized to maintain the fluidity of the formulation before administration and

resulting in gelation, when the formulation is administered in stomach.[26]

Guar gum

Properties

Guar gum is a naturally occurring gum which is also called as guaran which is obtained from

the endosperm of the seed. Guar gum is soluble in water but insoluble in hydrocarbons, fats,

esters, alcohols and ketones. It shows its dispersibility in both hot and cold water that is it is

soluble in both hot and cold water to form colloidal solution at low amount. Guar gum has

derivatives that are used in targeted delivery systems in the formation of coating matrix

systems, nano-microparticles and hydrogels. Guar gum also has derivatives such as graft

polymers like polyacrylamide grafted guar gums that have good colon targeting properties.

Guar gum can also be used as a polymer in matrix tablets which shows controlled release.

The semi synthetic form of guar gum is carboxy methyl guar(CMG) which is anionic in

nature that are used in formulation of transdermal drug delivery systems because it shows

good release rate profile, safety and stability. Guar gum is also available in various cross

linked forms that are used in various novel formulations i.e, glutyraldehyde cross linked guar

gum, hydroxyl ethyl guar gum, poly acrylic acid conjugate guar gum, hydroxyl methyl gum;

4-vinyl pyridine conjugated guar gum. The modified guar gum has potential to prevent cancer

by inhibiting carcinogen activating enzymes and promoting the carcinogen detoxification

enzyme glutathione-s-transferase.[27]

Mechanism

As guar gum has the capability of forming high viscous solution at low concentrations, the

galactose side chains that are attached to mannose backbone interact with water molecules

that are present in the solution leading to the formation of inter molecular chain which causes

entanglement of gaur gum molecules that are present in the aqueous phase causing the

formation of gelling or thickening of the solution. As guar gum is soluble in both hot water

and cold water, temperature plays a key role in the formation of gelling in the solution. So,


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increase in temperature causes reduction in gelling property of guar gum. As the temperature

reduces and causes the formation of sol. So, temperature causes reversible change in gelling

of gaur gum.[28]

Carbopol

Fig 5: Structure of carbopol

Properties

Carbopol is a polyacrylic acid (PAA) polymer, which changed to gel as the pH is raised from

4.0 to 7.4. Carbopol remains in solution form at acidic pH but transform into a low viscosity

gel at alkaline pH. HPMC is used in combination with carbopol which enhance viscosity of

carbopol solution, while reducing the acidity of the solution. Comparing different types of

poly (acrylic acid) (Carbopol 940-934-941and 910) 47 concluded that Carbopol 940 showed

superior appearance and clarity.[29]

Mechanism

At specific pH there is hydrophobic, electrostatic interaction and hydrogen bonding takes

place, hence leads to inter diffusion. The phase transition for carbopol solution was mediated

by the raise of pH from 4.0 to 7.4 which is due to ionization of Carbopol polymer. At pH 7.4,

the mutual repulsion of ionized carboxyl groups may produce more stretched carbopol

network and those carboxyl groups may also form stable hydrogen bonds with water

molecules through hydrophilic interactions.[30]

On the other hand, the hydrophobic nature of

carbopol backbone may form hydrophobic interchain aggregation; this cross-linking

phenomenon may result in transformation of viscous gel at pH 7.4 environment.[31]

Xyloglucan

Fig 6: Structure of Xyloglucan


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Properties

Xyloglucan is consists of three different oligomers like heptasaccharide, octasaccharide,

nonsaccharide, which differ in number of galactose side chain. It is widely used in oral,

rectal, ocular drug delivery due to its nontoxicity, biodegradable and biocompatible

property. Like, poloxamer it exhibit gelation on heating refrigerator temperature or cooling

from a higher temperature. But the difference is xyloglucan forms gel at lower concentration

(1-2%wt).[32]

Mechanism

In native form of xyloglucan does not show gelation, its dilute solutions form so-gel

transition on heating due to partial degradation of β-galactosidase. The transition temperature

is inversely related to galactose removal ratio and polymer concentration.[33]

Gellan gum

Fig 7: Structure of Gellan gum

Properties

Gellan gum is an anionic hetero polysaccharide, secreted by microbe Sphingomonas elodea.

It consists of glucose, rhamnose, glucuronic acid and are linked together to give a

tetrasaccharide unit.[34]

Gelrite is deacetylated gellan gum, obtained by treating gellan gum

with alkali to remove the acetyl group in the molecule. Upon instillation, gelrite forms gel

due to the presence of calcium ions. The gelation involves the formation of double helical

junction zones followed by aggregation of double helical segment to form three dimensional

networks by complexaton with cations and hydrogen bonding with water. Because of its

thixotropy, thermo plasticity, pseudo plasticity are widely use in ophthalmology. In food

industry, is used as suspending and stabilizing agent.[35]

Mechanism

Gellan gum produce a cation induced in situ gelation (Ca2+, Mg 2+, K+, Na+) due to the

cross linking between negatively charged helices and mono or divalent cations (Na+, Ca+,


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Mg+). Divalent ions superior to promoting gelation as compared to monovalent cations.

Gelation prolongs the residence time of drug at absorption site and bioavailability of the drug

is increased.[36]

Alginic acid

Properties

Alginic acid is a linear block copolymer polysaccharide consisting of β-D-mannuronic acid

and α-L-glucuronic acid residues joined by 1,4-glycosidic linkages. The proportion of each

block and the arrangement of blocks along the molecule vary depending on the algal source.

Dilute aqueous solutions of alginates form firm gels on addition of diandtrivalent metal ions

by a cooperative process involving consecutive glucuronic residues in the α-L glucuronicacid

blocks of the alginate chain.[37]

Alginic acid can be chosen as a vehicle for ophthalmic

formulations, since it exhibits favorable biological properties such as biodegradability and

nontoxicity. A prolonged precorneal residence of formulations containing alginic acid was

looked for, not only based on its ability to gel in the eye, but also because of its

mucoadhesive properties.[38]

Mechanism

Alginate is a copolymer with two types of monomers used, β- D-mannuronic acid (M) and α-

L-guluronic acid (G), arranged as homopolymeric blocks of M-M blocks or G-G blocks

together with blocks of alternating sequence (M-G). The polymer forms 3- dimensional

ionotropic hydrogel matrices, mostly by the interaction of calcium ions with G moieties

which leads the formation of inhomogeneous gel. The characteristic properties of these

hydrogels, such as mechanical strength and porosity, are dependent upon the G:M ratios,

concentration and viscosity of the initial alginate solution and type of ionic cross-linker (bi-

or polyvalent cations) etc.53, 54 Alginate with a high G content will improve the gelling

properties and reduce the total polymer to be introduced into the eyes.[39]

Xanthum gum

Properties

Xanthan gum is a high molecular weight extra cellular polysaccharide produced by the

fermentation of the gram-negative bacterium Xanthomonas campestris. The primary structure

of this naturally produced cellulose derivative contains a cellulosic backbone (β- D-glucose

residues) and a trisaccharide side chain of β-D-mannose-β-D-glucuronicacid-α-D-mannose

attached with alternate glucose residues of the main chain.[40]


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Mechanism

The degree of substitution for pyruvate usually varies between 30 and 40% whereas it is as

high as 60–70% for acetate. The anionic character of this polymer is due to the presence of

both pyruvic acid and glucuronic acid groups in the side chain. the drug release was the result

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

drug and polymer.[41]

Chitosan

Fig 8: Structure of Chitosan

Properties

Chitosan is a biodegradable, thermosensitive, polycationic polymer obtained by alkaline

deacetylation of chitin, a natural component of shrimp and crab shell. Chitosan is a

biocompatible pH dependent cationic polymer, which remains dissolved in aqueous solutions

up to a pH of 6.2. Neutralization of chitosan aqueous solution to a pH exceeding 6.2 leads to

the formation of a hydrated gel like precipitate. The pH gelling cationic polysaccharides

solution are transformed into thermally sensitive pH dependent gel forming aqueous

solutions, without any chemical modification or cross linking by addition of polyol salts

bearing a single anionic head such as glycerol, sorbitol, fructose or glucose phosphate salts to

chitosan aqueous solution.[42]

Mechanism

Gelling of chitosan occurs by two changes such as pH responsive change and temperature

change. Chitosan consists of ionic pendant groups which ionize and form network with

electrostatic forces. The gelling mechanism based on temperature changes at low critical

solution temperature. At this temperature due to extreme hydrophobic interactions gels are

formed. At upper critical solution temperature due to cooling of polymer solution gels are

formed. So, low critical solution temperature exhibiting polymers are used for gelation

process of chitosan.[43]


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HPMC

Fig 9: Structure of HPMC

Properties

Cellulose is composed of glucan chain with repeating β-(1,4)-D-glucopyranose unit. Natural

polymers like HPMC, MC and EC exhibit temperature sensitive sol-gel phase transition.

Cellulose material will increases its viscosity when temperature is decreases while its

derivatives like HPMC, MC, will increase its viscosity when temperature is increased. MC is

composed of native cellulose with alternate methyl substitution group on its chain. At low

temperature (300c) solution is in liquid form and when temperature is increases (40-50

0c)

gelation occurred.[44]

Mechanism

Gelation of cellulose solution is caused by hydrophobic interactions between molecules

containing methoxy substitution. At low temperature, molecules are hydrated and little

polymer-polymer interaction occurs, whereas at high temperature, polymers lose their water

of hydration.[45]

Poloxamer

Poloxamer are water soluble tri-block copolymer consisting of two polyethylene oxide (PEO)

and polypropylene oxide (PPO) core in an ABA configuration.[46]

Fig 10: Structure of Poloxamer

Properties

It is commercially available as Pluronic and has good thermal setting property and increased

drug residence time. It is used as gelling agent, emulsifying agent and solubilizing agent.


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Poloxamer gives colourless, transparent gel .Depending upon the ratio and distribution of

hydrophilic and hydrophobic chain several molecular weights available, having different

gelling property.[47]

Mechanism of gelling action

It consists of central hydrophobic part (polypropylene oxide) surrounded by hydrophilic part

(polyethylene oxide). At room temperature (25oC), it behaves as viscous liquid and is

transformed to transparent gel when temperature increases (37oC). At low temperature, it

forms small micellar subunit in solution and increase in temperature results increase in

viscosity leads to swelling to form large micellar cross linked network.[48,49]

Fig 11: Gelling mechanism of Poloxamer

APPLICABILITY OF IN SITU POLYMERIC DRUG DELIVERY SYSTEM

ORAL DRUG DELIVERY SYSTEM

The pH-sensitive hydro gels have a potential use in site-specific delivery of drugs to specific

regions of the GI tract. Hydrogels made of varying proportions of PAA derivatives and cross

linked PEG allowed preparing silicone microspheres, which released prednisolone in the

gastric medium or showed gastro protective property. Cross-linked dextran hydrogels with a

faster swelling under high pH conditions, likewise other polysaccharides such as amidaded

pectin’s, guar gum and inulin were investigated in order to develop a potential colon-specific

drug delivery system. The formulations of gellan and sodium alginate both containing

complexed calcium ions that undergo gelation by releasing of these ions in the acidic

environment of the stomach. Oral delivery of paracetamol was studied. For the oral in situ gel

delivery system pectin, xyloglucan & gellan gum natural polymers are used. Pectin

formulation for sustained delivery of paracetamol has been reported. Advantages of pectin is

water soluble so, no need to add organic solvent.[50]

OCULAR DRUG DELIVERY SYSTEM

In ocular delivery system natural polymers like gellan gum, alginic acid & xyloglucan are

most commonly used. For local ophthalmic delivery system various compounds like


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antimicrobial agent, anti-inflammatory agent & autonomic drugs are used to relieve intra

ocular tension in glaucoma. Conventional delivery system often result in poor availability &

therapeutic response because high tear fluid turn over & dynamics which cause rapid

elimination of the drug from the eye so, the overcome the bioavailability problem ophthalmic

in-situ gel were developed. To improve the bioavailability viscosity enhancers such as

Hydroxy Propyl Methyl Cellulose, Carboxy Methyl Cellulose, Carbomers, Poly Vinyl

alcohol used to increase the viscosity of formulation in order to prolong the precorneal

residence time & improve the bioavailability, easy to manufacture. Penetration enhancer such

as preservatives, chelating agent, surfactants are used to enhance corneal drug penetration.[51]

NASAL DRUG DELIVERY SYSTEM

In nasal in-situ gel system gallan gum & xanthan gum are used as in-situ gel forming

polymers Momethasone furoate was evaluated for its efficacy for the treatment of allergic

rhinitis. Animal study were conducted using allergic rhinitis model & effect of in-situ gel on

antigen induced nasal symptoms in sensitizes rats was observed. In-situ gel was found to

inhibit the increase in nasal symptoms are compared to marketed preparation nosonex

(Momethasone furoate suspension 0.05%).[52]

RECTAL DRUG DELIVERY SYSTEM

The rectal route may be used to deliver many types of drugs that are formulated as liquid,

semisolid (ointments, creams and foams) and solid dosage forms (suppositories).

Conventional suppositories often cause discomfort during insertion. In addition, suppositories

are unable to be sufficiently retained at a specific position in the rectum, sometimes they can

migrate up-wards to the colon that makes them possible for drug to undergo the first-pass

effect. Novel in situ gelling liquid suppositories with gelation temperature at 30–36°C.

Poloxamer 407 and/ or poloxamer 188 were used to confer the temperature-sensitive gelation

property. In-situ gel possesses a potential application for rectal & vaginal route. The use of

xyloglucan based thermo reversible gel for rectal drug delivery of Indomethacin.

Administration of Indomethacin loaded xyloglucan based system to rabbit indicated broad

drug absorption & a longer drug residence time as compared to that resulting after

administration of commercial suppository. For better therapeutic efficacy & patient

compliance, mucoadhesive, thermo sensitive, prolonged release vaginal gel incorporating

Clotrimazole-β-cyclodextrin complex formulated for treatment of vaginitis.[53]


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INJECTABLE DRUG DELIVERY SYSTEM

One of the most obvious ways to provide sustained- release medication is to place the drug in

delivery system and inject or implant the system into the body tissue. Thermoreversible gels

mainly prepared from poloxamers are predominantly used. The suitability of poloxamer gel

alone or with the addition of hydroxypropyl methylcellulose (HPMC), sodium

carboxymethylcellulose (CMC) or dextran was studied for epidural administration of drugs in

vitro. The compact gel depot acted as the rate limiting step and significantly prolonged the

Dural permeation of drugs in comparison with control solutions. Evaluated Pluronic F127

gels, which contained either insulin or insulin-PLGA nanoparticles with conclusion, that

these formulations could be useful for the preparation of a controlled delivery system.

Likewise, poloxamer gels were tested for intramuscular and subcutaneous administration of

human growth hormone or with the aim to develop a long acting single dose injection of

lidocaine. New class of injectable controlled release depots of protein which consisted of

blends of Pluronics with poly (D, L-lactide)/ 1- methyl-2- pyrrolidone solutions. Some other

thermosensitive hydrogels may also be used for parenteral administration. ReGel (triblock

copolymer PLGAPEG- PLGA) was used as a drug delivery carrier for the continuous release

of human insulin. Steady amounts of insulin secretion from the Re- Gel formulations up to

day 15 of the subcutaneous injections were achieved. Reported the synthesis of a

biodegradable poly (ethylene oxide) and poly (L-lactic acid) hydrogel, which exists in a form

of sol at an elevated temperature (around 45°C) and forms a gel after subcutaneous injection

and subsequent rapid cooling to body temperature. In-situ forming Injectable drug delivery

system, crosslinking of hydrazide modified by aluronic acid with aldehyde modified version

of cellulose derivatives such as carboxy methyl cellulose, methyl cellulose, hydroxy

propylmethyl cellulose are used. These in-situ forming gel were used for preventing

postoperative peritoneal adhesion thus avoiding pelvic pain, bowel obstruction & infertility.

For a better therapeutic efficacy & patient compliance, mucoadhesive, thermo sensitive,

prolonged release vaginal gel incorporating Clotrimazole-β- cyclodextrin complex was

formulated for treatment of virginities.[54]

DERMAL AND TRANSEDERMAL DRUG DELIVERY

Thermally reversible gel of Pluronic F127 was evaluated as vehicle for the percutaneous

administration of Indomethacin. In-vivo studies suggest that 20% w/w aqueous gel may be of

practical use as a base for topical administration of the drug. Poloxamer 407 gel was found


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suitable for transdermal delivery of insulin. The combination of chemical enhancers and

iontophoresis resulted in synergistic enhancement of insulin permeation.[55]

REFERENCES

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Pharmagene., 2014; 2(4): 29-33.

2. F. Suisha, N. Kawasaki, S. Miyazaki, M. Shirakawa, K. Yamatoya, M. Sasaki, D.

Attwood, Xyloglucan gels as sustained release vehicles for the intraperitoneal

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