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CHAPTER 3

Polymer Profile

Chapter 3 Polymer Profile

58 | B H A G W A N T U N I V E R S I T Y , A J M E R

POLYMER PROFILE

3.1. CHITOSAN

Chitosan is a natural polymer obtained by de-acetylation of chitin. Chitin is the

second most abundant polysaccharides in nature after cellulose. The main commercial

sources of chitin are the shell wastes of shrimp, crab, lobster, krill, and squid. It is a

biologically safe, non-toxic, biocompatible, and biodegradable polysaccharide. Being

a bioadhesive polymer and having antibacterial activity, chitosan is a good candidate

for site-specific drug delivery. It has mucoadhesive properties due to its positive

charges at neutral pH that enable an ionic interaction with the negative charges of

sialic acid residues of the mucus.

Chitin is similar to cellulose both in chemical structure and in biological function as a

structural polymer. The crystalline structure of chitin has been shown to be similar to

cellulose in the arrangements of inter- and intra-chain hydrogen bonding. Chitosan is

made by alkaline N-deacetylation of chitin. The term chitosan does not refer to a

unique defined compound; it merely refers to a family of copolymers with various

fractions of acetylated units. It consists of two types of monomers; chitin-monomers

and chitosan-monomers. Chitin is a linear polysaccharide consisting of (1-4)-linked 2-

acetamido-2-deoxy-b-D-glucopyranose. Chitosan is a linear polysaccharide consisting

of (1-4)-linked 2-amino-2-deoxy-b-D-glucopyranose.

Commercial chitin and chitosan consists of both types of monomers. Chitin and

chitosan are both prepared using the common process illustrated and described as

follows-

Chapter 3


Shellfish wastes from

Decalcification in dil. aqueous HCl solution (3

Deproteination in dil. aqueous NaOH solution (3

room temperature overnight)

Decolarization in 0.5%

Deacetylation in hot concentrate NaOH solution (40

4-5 hrs)

Polymer Profile

B H A G W A N T U N I V E R S I T Y , A J M E R

Shellfish wastes from shrimp, crab and squid

Decalcification in dil. aqueous HCl solution (3-5% w/v HCl at room temperature)

Deproteination in dil. aqueous NaOH solution (3-5% w/v NaOH at 80

room temperature overnight)

Decolarization in 0.5% aqueous KMnO4

Chitin

Deacetylation in hot concentrate NaOH solution (40-50% w/v NaOH at 90

CHITOSAN

Polymer Profile

5% w/v HCl at room temperature)

5% w/v NaOH at 80-900C or at

50% w/v NaOH at 90-1200

C for



3.2. Applications of Chitosan

3.2.1. Buccal Delivery- Chitosan is an excellent polymer to be used for buccal

delivery because it has mucoadhesive/bioadhesive properties and can act as an

absorption enhancer. Bioavailability and residence time of the drugs that are

administered via the buccal route can be increased by bioadhesive drug delivery

systems.

3.2.2. Ophthalmic Delivery- Various studies showed the potential of chitosan-based

systems for improving the retention and bio-distribution of drugs applied topically

onto the eye. In addition to its low toxicity and good ocular tolerance, chitosan

exhibits favorable biological behavior, such as bioadhesion, permeability-enhancing

properties, and interesting physico-chemical characteristics, which make it a unique

material for the design of ocular drug delivery vehicles (lonso et al., 2003).

3.2.3. Nasal Delivery- The nasal mucosa presents an ideal site for bioadhesive drug

delivery systems (Turker et al., 2004). Chitosan drug delivery systems, such as

microspheres, liposomes, and gels, have been demonstrated to have good bioadhesive

characteristics and swell easily when in contact with the nasal mucosa. Bioavailability

and residence time of the drugs that are administered via the nasal route can be

increased by bioadhesive drug delivery systems. Various chitosan salts (chitosan

lactate, chitosan aspartate, chitosan glutamate, and chitosan hydrochloride) showed

nasal sustained release of vancomycin hydrochloride. Chitosan delivery systems (such

as microspheres) have the ability to increase the residence time of drug formulations

in the nasal cavity, thereby providing the potential for improved systemic medication

(Soane et al., 2001). Diphtheria toxoid (DT) associated to chitosan microparticles

results in protective systemic and local immune response against DT, and enhances

significant IgG production after nasal administration.

3.2.4. Buccal Delivery- An ideal buccal delivery system should stay in the oral cavity

for a few hours and release the drug in a unidirectional way toward the mucosa in a

controlled- or sustained-release fashion. Mucoadhesive polymers will prolong the

residence time of the device in the oral cavity. Bilayered devices will ensure the

release of the drug occurs in a unidirectional way (Nagai et al., 1993 & Anders et al.,

1989).

Chitosan is an excellent polymer to be used for buccal delivery because it has

muco/bioadhesive properties and can act as an absorption enhancer. Directly

compressible bioadhesive tablets of ketoprofen containing chitosan and sodium



alginate in the weight ratio 1:4 showed sustained release 3 hours after intraoral

(sublingual site of rabbits) drug administration. Buccal tablets based on chitosan

microspheres containing chlorhexidine diacetate showed a prolonged release of the

drug in the buccal cavity. The loading of chlorhexidine into chitosan is able to

maintain or improve the antimicrobial activity of the drug. The improvement is

particularly high against Candida albicans. This is important for a formulation whose

potential use is against buccal infections. Drug-empty microparticles have an

antimicrobial activity due to the chitosan itself. The buccal bilayered devices

(bilaminated films, bilayered tablets) using a mixture of drugs (nifedipine and

propranolol hydrochloride) and chitosan, with or without anionic cross linking

polymers (polycarbophil, sodium alginate, gellan gum), demonstrated that these

devices show promising potential for use in controlled delivery of drugs to the oral

cavity. Bioadhesive tablets of nicotine containing 0% to 50% w/w glycol chitosan

produced the good adhesion.

3.2.5. Periodontal Delivery- Local delivery of drugs and other bioactive agents

directly into the periodontal pocket has received a lot of attention lately. For example,

for moderate to severe periodontal diseases, antimicrobial agents are used to eradicate

and/or suppress the plaque bacteria. However, systemic administration of these drugs

has certain disadvantages, such as the necessity for frequent dosing to maintain the

drug concentrations at the therapeutic level in the plasma, poor patient compliance,

super infections caused by resistant organisms, and gastrointestinal and systemic side-

effects. An ideal formulation should be easy to deliver, have good retention at the

target site, and provide sustained release of the drug. Mucoadhesive/bioadhesive

polymers increase the residence time of the formulation in the oral cavity. This will

enhance drug penetration, localize the drug for local therapy, target the diseased

tissue, and improve efficacy and acceptability.

3.2.6. Gastrointestinal (Floating) Drug Delivery- Floating systems have a density

lower than the density of the gastric juice. Thus, gastric residence time and hence the

bioavailability of drugs that are absorbed in the upper part of the GI tract will be

improved. Intragastric floating dosage forms are useful for the administration of drugs

that have a specific absorption site, area insoluble in the intestinal fluid, or area used

for the treatment of gastric diseases. Chitosan granules having internal cavities were

prepared by deacidification. When added to acidic (pH 1.2) and neutral (deionized

distilled water) media, these granules were immediately buoyant and provided a



controlled release of the candidate drug prednisolone. Both chitosan granules and

chitosan-laminated preparations could be helpful in developing drug delivery systems

that will reduce the effect of gastrointestinal transit time. Floating hollow

microcapsules of melatonin produced have an interesting gastroretentive controlled-

release delivery system for drugs. Release of the drug from these microcapsules was

greatly retarded with release lasting for several hours (1.75 to 6.7 hours in simulated

gastric fluid), depending on processing factors. Most of the hollow microcapsules

developed tended to float over simulated bio-fluids for more than 12 hours

3.2.7. Peroral Drug Delivery- Because of the mucoadhesive properties of chitosan

and most of its derivatives, a pre-systemic metabolism of peptides on the way

between the dosage form and the absorption membrane can be strongly reduced.

Based on these unique features, the co-administration of chitosan and its derivatives

leads to a strongly improved bioavailability of many per-orally given peptide drugs,

such as insulin, calcitonin, and buserelin. Unmodified chitosan proved to display a

permeation-enhancing effect for peptide drugs. A protective effect for polymer-

embedded peptides toward degradation by intestinal peptidases can be achieved by

the immobilization of enzyme inhibitors on the polymer. Serine proteases are

inhibited by the covalent attachment of competitive inhibitors, such as the Bowman-

Birk inhibitor; metallo-peptidases are inhibited by chitosan derivatives displaying

complexing properties, such as chitosan-EDTA conjugates. Chitosan films are an

alternative to pharmaceutical tablets.

(Chandy et al., 1992)

3.2.8. Intestinal Drug Delivery- Sustained intestinal delivery of drugs, such as 5-

fluorouracil (choice for colon carcinomas) and insulin (for diabetes mellitus), seems

to be a feasible alternative to injection therapy. A formulation was developed that

could bypass the acidity of the stomach and release the loaded drug for long periods

into the intestine by using the bioadhesiveness of polyacrylic acid, alginate, and

chitosan. Bromothymol blue was taken as a model drug. The formulation exhibited

bioadhesive property and released the drug for an 80-day period in vitro.

Chitosan/calcium alginate microcapsules containing nitrofurantoin (NF) showed

sustained release of drug. Drug release into the gastric medium is found to be

relatively slow compared to that into the intestinal medium (Hari et al., 1996).

3.2.9. Colon Delivery- Chitosan was used in oral drug formulations to provide

sustained release of drugs. Recently, it was found that chitosan is degraded by the



microflora that is available in the colon. As a result, this compound could be

promising for colon-specific drug delivery. Chitosan was reacted separately with

succinic and phthalic anhydrides. The resulting semi-synthetic polymers were proved

for colon-specific, orally administered drug delivery systems. Systems for colon

delivery containing acetaminophen (paracetamol), mesalazine (5-ASA), sodium

diclofenac, and insulin have been studied and showed satisfactory results (ozaki et al.,

2002).

3.2.10. Vaginal Delivery- Chitosan, modified by the introduction of thioglycolic acid

to the primary amino groups of the polymer, embeds clotrimazole, an imidazole

derivative widely used for the treatment of mycotic infections of the genitourinary

tract. By introducing thiol groups, the mucoadhesive properties of the polymer were

strongly improved, and this resulted in an increased residence time of the vaginal

mucosa tissue (26 times longer than the corresponding unmodified polymer),

guaranteeing a controller drug release in the treatment of mycotic infections. Vaginal

tablets of chitosan containing metronidazole, acriflavine, and other excipients showed

adequate release and good adhesion properties (El-Kamel et al., 2002).

3.2.11. Transdermal Delivery- Chitosan has good film-forming properties. The drug

release from the devices is affected by the membrane thickness and cross-linking of

the film. Chitosan-alginate poly electrolyte complex (PEC) has been prepared in situ

in beads and microspheres for potential applications in packaging, controlled release

systems, and wound dressings. Chitosan gel beads are a promising biocompatible and

biodegradable vehicle for treatment of local inflammation. Chitosan gel beads

containing the anti-inflammatory drug prednisolone showed sustained release of drug

with reduced inflammation indexes that resulted in improved therapeutic efficacy.

(Thein-Han et al., 2004).

3.2.12. Vaccine Delivery- Various chitosan-antigen nasal vaccines have been

prepared. These include cholera toxin, microspheres, nanoparticles, liposomes,

attenuated virus and cells, and outer membrane proteins (proteosomes). They induced

significant serum IgG responses similar to and secretory IgA levels superior to what

was induced by a parenteral administration of the vaccine. Chitosan microparticles are

very promising mucosal vaccine delivery systems. Significant systemic humoral

immune responses were found after nasal vaccination with diphtheria toxoid

associated to chitosan microparticles. Diphtheria toxoid associated to chitosan

microparticles results in protective systemic and local immune response against



diphtheria toxoid after oral vaccination and in significant enhancement of IgG

production after nasal administration. Chitosan microspheres cross-linked with

glutaraldehyde were loaded by bovine serum albumin (BSA) and diphtheria toxoid

and showed tissue compatibility with a long-lasting drug delivery system in wistar

rats for several days (Ameela et al., 1994).…………………………………….



Table 3.1: Chitosan based drug delivery system prepared by different methods for various kinds of drugs.

S.No. Type of System Method drugs

1. Films/ Patch(Ganesh et al. 2008)

Solvent casting isosorbide dinitrate, chlorhexidine gluconate, trypsin,

granulocyte-macrophage colony-stimulating factor, acyclovir,

riboflavine, testosterone, progesterone, beta-oestradiol,

metoprolol, propanolol.

2. Tablet(Gavini et al. 2002) Matrix coating Diclofenac, pentoxyphylline, salicylic acid,

theophylline,propranolol HCl

3. Capsule(Patil et al. 2009) Capsule Shell insulin, 5-amino salicylic acid

4. Microspheres/Microparticles

(Prabhaharan et al. 2005)

emulsion cross-linking theophylline, cisplatin, pentazocine, phenobarbitone,

theophylline,

insulin, 5-fluorouracil, diclofenac sodium, griseofulvin, aspirin,

diphtheria toxoid, pamidronate, suberoylbisphosphonate,

mitoxantrone, progesterone

coacervation/precipitation prednisolone, interleukin-2, propranolol-HCl

ionic gelation felodipine

5. Nanoparticles (Rathore et al. 2011 &

Yassin et al. 2006)

emulsion-droplet

coalescence

coacervation/precipitation

ionic gelation, reverse

micellar method

gadopentetic acid

DNA, doxorubicin,

insulin, ricin, bovine serum albumin, cyclosporin A, doxorubicin

6. Beads(Yassin et al. 2006) coacervation/precipitation adriamycin, nifedipine, bovine serum albumin, salbutamol

sulfate, lidocaine– HCl, riboflavin

7. Gel(Patel et al. 2010) cross-linking chlorpheniramine maleate, aspirin, theophylline, caffeine,

lidocaine– HCl, hydrocortisone acetate, 5-fluorouracil



3.3. Recent work on Chitosan

Modified chitosan was used for the formation of acylated chitosan nanoparticles by

ionic cross linking method using sodium tripolyphosphate as cross linking agent and

albendazole was selects as a drug molecule. The structure acylated chitosan was

examined by FT-IR, and X-ray diffraction analysis, and the data compared to those of

native chitosan. Prepared nanoparticles were characterized in terms of morphology

and drug loading efficiency (Rathore et al., 2011). A discussed was made on the

preparation and characterization of Chitosan with their applicability in pharmaceutical

formulations. Different derivatives of Chitosan and their use in different drug delivery

system were also explained (Bansal et al., 2011). The chemical modification of chitin

and chitosan and the role of individual functional groups in applications of modified

chitosan from the viewpoint of biomedical applications were discussed. Chitosan

attached to sugars, dendrimers, cyclodextrins, crown ethers, and glass beads. Sugar-

modified chitosans were excellent candidates for drug delivery systems or cell culture

owing to their specificity (Sashiwa et al., 2004). Chitosan is a natural polymer

obtained by deacetylation of chitin it is the second most abundant polysaccharides in

nature after cellulose. Main commercial sources of chitin were the shell wastes of

shrimp, crab, lobster, krill, and squid. It is a biologically safe, non-toxic,

biocompatible, and biodegradable polysaccharide. Being a bioadhesive polymer and

having antibacterial activity, chitosan is a good candidate for site-specific drug

delivery (Patel et al., 2008). In the chemical structure of chitosan and found that the

primary hydroxyl and amine groups located on the backbone of chitosan allow for

chemical modification to control its physical properties. When the hydrophobic

moiety is conjugated to a chitosan molecule, the resulting amphiphile may form self-

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

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

functional linker may produce useful prodrugs (Kushwaha et al., 2010). Delivery of

insulin with chitosan was investigated and found that the chitosan and its derivatives

or salts have been widely used as functional excipients of delivering insulin via oral,

nasal and transdermal routes. Chitosan for its mucoadhesive property protect the

insulin from enzymatic degradation, prolong the retention time of insulin, as well as,

open the inter-epithelial tight junction to facilitate systemic insulin transport (Wong et

al., 2009). A chitosan based novel drug delivery system was formed because chitosan

is a natural polymer obtained by alkaline de-acetylation of chitin. It is a non-toxic,



biocompatible and biodegradable polymer, because of these properties it is easily used

in novel drug delivery system (Prabhaharan et al., 2005). New extended release

gastroretentive mutiparticulate delivery system for verapamil (VP) was developed by

incorporation into hydrogel beads made of chitosan. Prepared beads were

characterized for sizes, shapes, friability and loading efficiencies. Preparation of

chitosan beads using this technique would provide a simple and commercially viable

method of preparation of chitosan beads for controlling the release of some drugs

(Yassin et al., 2006). Alginate microcapsules coated with mucoadhesive polymer

chitosan was developed by ionotropic gelation technique utilizing calcium chloride

(CaCl2) as a cross linking agent, to take the advantage of swelling and mucoadhesive

property of alginate beads for improving the oral delivery of gliclazide. The prepared

microcapsules coated with mucoadhesive polymer chitosan exhibited good

mucoadhesive property in the in vitro wash off test and also showed high percentage

drug entrapment efficiency (Patil et al., 2009). Conventional PLGA was coated by

solvent extraction process by means of a biocompatible cationic polyelectrolyte, e.g.

chitosan, using a static micromixer. This one-step procedure can easily be performed

aseptically. In a second step the functional groups of the hydrocolloidal chitosan shell

provide the possibility to bioconjugate various bioactive ligands, e.g. sugars,

antibodies or peptides, to the surface. Such modular synthetic carriers may pave the

way to targeted delivery of microparticulate drug delivery systems (Fischer et al.,

2004). An alternative chitosan nanoparticle-based therapeutic system of aldehyde

acrolein, was evaluated, which is a very potent endogenous toxin with a long half-life

and it is produced within cells after insult, and is a central player in slow and

progressive “secondary injury” cascades. Indeed, acrolein-biomolecule complexes

formed by cross-linking with proteins and DNA are associated with a number of

pathologies, especially CNS trauma and neurodegenerative diseases (Borgens et al.,

2010). Chitosan nanoparticles have gained more attention as drug delivery carriers

because of their better stability, low toxicity, simple and mild preparation method and

providing versatile routes of administration. Their sub-micron size is also suitable for

mucosal routes of administration i.e. oral, nasal and ocular mucosa which is non-

invasive route (Sailaja et al., 2010). Chitosan nanoparticles labelled with fluorescein

isothiocyanate-bovine serum albumin were prepared by ionotropic gelation, a new

particulate drug carrier, with epithelial cells on the ocular surface. The nanoparticles

were well tolerated by the ocular surface tissues. These facts added further support for



the potential use of these colloidal systems to delivery drugs to the ocular surface

(Salamanca et al., 2006). In the biomedical engineering field, namely as a drug

delivery carrier for biopharmaceuticals chitosan nanoparticles are used. Chitosan is a

rather abundant material, which has been widely used in food industrial and bio-

engineering aspects, including in encapsulating active food ingredients, in enzyme

immobilization, and as a carrier for drug delivery, due to its significant biological and

chemical properties such as biodegradable, biocompatible, bioactive, and polycationic

(Tang et al., 2011). Superporous hydrogel composite are used for floating and

sustained delivery of Ranitidine hydrochloride. The prepared hydrogel was

characterized for swelling index, mechanical strength, SEM, buoyancy study and in-

vitro release study. Prepared floating drug delivery system was promising for stomach

specific delivery of Ranitidine hydrochloride (Patel et al., 2010). Chitosan-alginate

nanoparticles were prepared by ionotropic pre-gelation of an alginate core followed

by chitosan polyelectrolyte complexation. Nifedipine was used as a model drug.

Morphology & Structure characterization of prepared nanoparticles were investigated

by TEM and FTIR, respectively. In addition, the delivery behaviour of nifedipine

from nanoparticles was also studied and they found that the release of nifedipine from

nanoparticles was pH-responsive (Ping et al., 2008). For improving its intracellular

targeting and thereby targeting the cancer cells, Cytarabine nanospheres of chitosan

were prepared. The nanospheres were characterized for particle size, drug loading and

% drug release. The release of drug from the matrix was by non-Fickian analomous

diffusion mechanism (Sangeetha et al., 2010). Nanocomposites polymer was used as

the drug carrier for delivery systems of anticancer drug. Chitosan and sodium alginate

with different ratios were blended with different wt % of Cloisite 30B solution by

solvent evaporation method. The drug release was studied by changing time, pH and

drug concentrations and the kinetics of the drug release was studied in order to

ascertain the type of release mechanism (Nayak et al., 2011). A novel chitosan –based

superabsorbent hydrogel via graft copolymerization of mixtures acrylic acid and N-

vinyl pyrollidon onto chitosan backbones was synthesized. Polymerization reaction in

an aqueous medium and in the presence of ammonium persulfate as an initiator and

N,N'-methylene bisacrylamide as a crosslinker was performed. Synthesized hydrogels

was an excellent candidate for controlled delivery of bioactive agents (Sadeghi et al.,

2011). Vaginal tablets of acriflavine were developed using drug-loaded chitosan

microspheres and excipients like methylcellulose, sodium alginate, sodium CMC, or



Carbopol 974. Microspheres was prepared by a spray-drying method and found that

the formulation containing microspheres with drug to polymer weight ratios of 1:1

and Carbopol 974 shows best release behavior and mucoadhesive properties (Gavini

et al., 2002). Many processes are used to encapsulate drugs within chitosan matrixes

such as ionotropic gelation, spray drying, emulsification-solvent evaporation and

coacervation. Combinations of these processes are also used in order to obtain

microparticles with specific properties and performances (Heras et al., 2008). The

positive charge is very important in chitosan drug delivery systems as it plays a very

important role in mucoadhesion. Other chitosan based drug delivery systems involve

complexation with ligands to form chitosan nanoparticles with can be used to

encapsulate active compounds (Morris et al., 2010). Supercritical fluid technology

was used for the preparation of chitosan. The physicochemical and biological

properties of chitosan make it an excellent material for the preparation of drug

delivery systems and for the development of new biomedical applications in many

fields from skin to bone or cartilage (Duarte et al., 2010). Pharmaceutical applications

of chitosan-based micro/nanoparticulate drug delivery systems published over the past

decade and also the methods of their preparation, drug loading, release characteristics,

and applications are covered. Chemically modified chitosan or its derivatives used in

drug delivery research were also discussed (Aminabhavi et al., 2004). Chitosan

nanoparticles are good drug carriers because of their good biocompatibility and

biodegradability. Chitosan nanoparticles have attracted increasing attention for their

wide applications in, for example, loading protein drugs, gene drugs, and anticancer

chemical drugs (Wang et al., 2011). Chitosan based hydrogel polymeric beads have

been extensively used as micro or nano particles in the pharmaceutical field, where

they have shown promise for drug delivery as a result of their controlled and sustained

release properties, as well as biocompatibility with tissue and cells (Negi et al., 2010).

Only cationic polysaccharide of natural origin, chitosan, a versatile biopolymer of the

amino glucopyran family is extensively used in pharmaceutical applications such as

nano or microparticles in oral or buccal delivery, stomach-specific drug delivery and

colon-specific drug delivery (Sonia et al., 2011). Different materials used for the

production of nanocarriers, chitosan enjoy high popularity due to its inherent

characteristics such as biocompatibility, biodegradability and mucoadhesion. On the

modification of chemical structure of chitosan it shows advantages for the delivery of

drug in pulmonary system (Andrade et al., 2011). N-trimethyl chitosan (TMC) was



synthesized with different degrees of quaternization (DQ). TMC saws characterized

with DQ of 40 and 60% (TMC40 and TMC60) by 1H NMR. Testosterone (TS) used

as an effective drug. Four different gels were prepared, and the results showed that

TMC60 could significantly affect the secondary structure of keratin in stratum

corneum (He et al., 2008). Bioadhesiveness of several chitosan chloride samples was

screened in-vitro and compared with HPMC, carbopol and polycarbophill by a force

detachment method. The adhesive interaction between chitosan and biological

membrane was depending upon chitosan quality and formulation factors (Henriksen et

al., 1999). Chitosan nanoparticles-containing microspheres were prepared for the

pulmonary administration of therapeutic macromolecules. Not only formulations

possess suitable aerodynamic characteristics and the capacity to encapsulate proteins

as shown previously; also shown to exhibit in vitro biocompatibility (Forbes et al.,

2007). Novel multifunctional non-cytotoxic chitosan derivatives, containing thiol

along with quaternary ammonium groups (N+-Ch–SH), with increased potential to

enhance transepithelial drug transport was synthesized. Multifunctional derivatives

have improved the ability of the parent N+-Chs to enhance the permeability of the

water-soluble macromolecular fluorescein isothiocyanate dextran (Colo et al., 2009).

Chapter 3


3.4. SODIUM CARBOXY METHYLE CELLULOSE

It is prepared from cellulose by

its sodium salt. It is also known as Sodium salt of carboxymethyl ether of cellulose.

Simply cellulose molecule composed of repeating cellobiose units. These inturn are

composed of two anhydroglucose unit

hydroxyl groups. By substituting carboxymethyl groups for some of the hydrogens of

these hydroxyls, sodium carboxymethyl cellulose is obtained

2011).

NaCMC are long chain polymers and their s

average chain length and degree of polymerization as well as the degree of

substitutions. Average chain length and degree of substitutions determine the

molecular weight of the polymer. As molecular weight increases vi

solution increases rapidly

The structural formula of NaCMC:

3.5. Properties of NaCMC

1. Its acts as a thickener, binder, stabilizer, protective colloids, suspending

rheology or flow control agent.

2. It forms films that are resistant to oil and organic solvents.

3. It dissolved rapidly in hot and cold water.

4. It is suitable for use in food system.

5. It is physiologically inert.

6. It is an anion electrolyte.

3.6. Uses of NaCMC

NaCMC is used in

to stabilize emulsions in various products including

of many non-food products, such as

based paints, detergents, textile

2007). It is used primarily because it has high

is hypoallergenic. In laundry detergents it is used as a soil suspension polymer

Polymer Profile

B H A G W A N T U N I V E R S I T Y , A J M E R

3.4. SODIUM CARBOXY METHYLE CELLULOSE (NaCMC)

It is prepared from cellulose by treatment with alkali and monochloro-acetic acid or



composed of two anhydroglucose units. Each anhydroglucose units contains three


these hydroxyls, sodium carboxymethyl cellulose is obtained (McConville et al.,

NaCMC are long chain polymers and their solution characteristics depend on the



molecular weight of the polymer. As molecular weight increases viscosity of the

solution increases rapidly (Bhanja et al., 2010).

The structural formula of NaCMC:

3.5. Properties of NaCMC

Its acts as a thickener, binder, stabilizer, protective colloids, suspending

rheology or flow control agent.

It forms films that are resistant to oil and organic solvents.

It dissolved rapidly in hot and cold water.

It is suitable for use in food system.

It is physiologically inert.

It is an anion electrolyte.

food science as a viscosity modifier or thickener

in various products including ice cream. It is also a constituent

food products, such as toothpaste, laxatives, diet

, textile sizing and various paper products (Ramana et al.,

. It is used primarily because it has high viscosity, is non

. In laundry detergents it is used as a soil suspension polymer

Polymer Profile

acetic acid or



s. Each anhydroglucose units contains three


(McConville et al.,

olution characteristics depend on the



scosity of the

Its acts as a thickener, binder, stabilizer, protective colloids, suspending agent and

thickener, and

. It is also a constituent

diet pills, water-

Ramana et al.,

, is non-toxic, and

. In laundry detergents it is used as a soil suspension polymer



designed to deposit onto cotton and other cellulosic fabrics creating a negatively

charged barrier to soils in the wash solution. CMC is used as a lubricant in non-

volatile eye drops.

NaCMC is also used in pharmaceuticals as a thickening agent. NaCMC is also used in

the oil drilling industry as an ingredient of drilling mud, where it acts as a viscosity

modifier and water retention agent. Poly-anionic cellulose or PAC is derived from

CMC and is also used in oilfield practice.

Insoluble microgranular carboxymethyl cellulose is used as a cation-exchange resin

in ion-exchange chromatography for purification of proteins. Presumably the level of

derivatization is much lower so that the solubility properties of microgranular

cellulose are retained while adding sufficient negative charged carboxylate groups to

bind positively charged proteins (Nakhat et al., 2007).

CMC is also used in ice packs to form a eutectic mixture resulting in a lower freezing

point and therefore more cooling capacity than ice.

Aqueous solutions NaCMC have also been used to disperse carbon nanotubes. It is

thought that the long NaCMC molecules wrap around the nanotubes, allowing them to

be dispersed in water.

3.7. Properties of NaCMC films

Clear films of NaCMC can be obtained by evaporating the water from the solution.

These flexible are unaffected by oils and organic solvents. Some times to improve the

flexibility and elongation of the films plasticizers are used, such as propylene glycol,

glycerol etc (Hirlekar et al., 2010).

3.8. Recent work on NaCMC

Buccal route of administration has a number of advantages including bypassing the

gastrointestinal tract and the hepatic first pass effect. A number of polymers for the

preparation of buccal films like sodium carboxymethyl cellulose (SCMC), hydroxy

propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), hydroxyethyl

cellulose (HEC), poly vinyl pyrrolidone (PVP), and chitosan were used. Buccal films

were characterized for mucoadhesive strength, drug content uniformity, and

permeation rate (McConville et al., 2011). Sodium carboxy methyl cellulose,

carbopol, and methocel K4M or K15M as mucoadhesive polymers were used for the

development of buccoadhesive bilayered tablet of terbutaline sulphate. Sodium

carboxy methyl cellulose used alone or in combination with ethyl cellulose. The

preparation containing carbopol and methocel K4M in the ratio of 1:1 could be used



to design effective and stable buccoadhesive tablets of terbutaline sulphate (Nakhat et

al., 2007). Buccoadhesive films of propanolol hydrochloride were prepared using

sodium carboxymethyl cellulose and poly methyl methacrylate as polymer while

glycerol as plasticizer. Films were prepared in such a way that the drug release in one

direction only (unidirectional flow). Tachycardia was induced with the help of

isoprenaline and checked the effect of propanolol hydrochloride through buccal route

(Pandit et al., 2001). Mucoadhesive bilayered buccal devices comprising of

methotrexate containing mucoadhesive layer and drug free backing membrane were

developed. Bilaminated patches were prepared that was composed of mixture of drug

and sodium alginate alone or in combination with sodium carboxymethylcellulose,

Polyvinyl Pyrrolidone, Carbopol 934 and backing membrane (ethyl cellulose). The

study showed that the combination of sodium alginate with carbopol 934 and glycerol

as plasticizer, gives promising results (Bhanja et al., 2010). Buccal films for the

delivery of netrendipine were developed by using polymers like sodium

carboxymethylcellulose, poly vinyl alcohol (PVA), HPMC K-100, sodium alginate

and carbopol 934P. The prepared films were evaluated for content uniformity, radial

swelling, surface pH, folding endurance and in-vitro drug release. The optimized film

showed moderate drug release i.e. 50% at the end of 2 hours (Nappinnai et al., 2008).

Fast dissolving drug delivery system (FDDS) is suited for the drugs which undergo

high first pass metabolism and is used for improving bioavailability with reducing

dosing frequency to mouth plasma peak levels. A number of polymers that were used

by different scientist for the preparation of buccal patches like gelatin, hydroxypropyl

methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl

pyrrolidone, carboxymethyl cellulose, polyvinyl alchohal, sodium alginate, xanthin

gum, tragacanth gum, guar gum, acacia gum (Mahajan et al., 2011). Mucoadhesive

buccal films of glipizide were prepared by solvent casting technique using hydroxy

propylmethyl cellulose, sodium carboxymethyl cellulose, carbopol- 934P and

Eudragit RL-100, prepared films were evaluated for their weight, thickness, surface

pH, swelling index, in vitro residence time, folding endurance, in vitro release, ex vivo

permeation studies and drug content uniformity. The films containing 5 mg glipizide

in 4.9 % w/v hydroxy propylmethyl cellulose and 1.5 % w/v sodium carboxymethyl

cellulose exhibited satisfactory swelling, an optimum residence time (Semalty et al.,

2008).



3.9. POLY VINYL ALCOHOL (PVA)

PVA is a water soluble resin produced by the hydrolysis of polyvinyl acetate, which

made by the polymerization of vinyl acetate monomer. It is generally in the form of

white granules or powder having the specific gravity 1.25 to 1.32 g/ml. Generally

PVA is not soluble in animal, plant & grease oils and also not in organic solvents, but

soluble in acid and alkali (Ismail et al., 2003).

PVA is classified into two main groups’ namely fully hydrolysed and partially

hydrolysed grade.

3.9.1. Fully hydrolysed PVA

It is dispersed easily in water without lumps because of low solubility at room

temperature. First charge the vessel with water, add the PVA with continuous stirring

at room temperature and then heat up to 95o C. PVA dissolved completely after

stirring within 30 to 90 min, depending on the effectiveness of stirring.

3.9.2. Partially hydrolysed PVA

Partially hydrolysed PVA is more likely to produce foam, so rapidly increased

temperature is to be avoided. It is dissolved in water at 90 o C, within 30-60 min. At

higher temperature the dissolution rate of the PVA may be increased.

3.10. Other Properties (Anilreddy et al., 2010, Basu et al., 2010, Nappinnai et al.,

2008)

3.10.1. Viscosity of Solution

As degree of polymerization and degree of hydrolysis increases, the viscosity of the

aqueous solution becomes higher, and depending largely on the degree of

polymerization rather than degree of hydrolysis.

3.10.2. Surface tension of solution

PVA aqueous solution decreases surface tension of water and has function as

protective colloid. Surface tension of PVA aqueous solution increases as the degree of

hydrolysis increases, but there is only a little change in degree of polymerization.



3.10.3. Adhesion of the solution

PVA having better adhesion properties as compare to the other water soluble

polymers. Aqueous solution of PVA has strong adhesion to hydrophilic substances

and the adhesion tends to increase with the increase in the degree of hydrolysis and

polymerization.

3.10.4. Thermal Properties

PVA changes to yellow in colour upon heating and rapidly decomposed above

205oC. The degree of Crystallinity increase proportional to the thermal temperature

and time.

3.10.5. Mechanical properties of PVA film

PVA film generally has good mechanical proprieties compared to the other polymeric

films. Mechanical properties are affected by relative humidity because of plasticizing

role of water.

3.10.6. Gelation

The gelation of PVA aqueous solution occurs even with a small quantity. The gelation

occurs easily with the high degree of hydrolysis concentration of PVA in aqueous

solution.

3.11. Recent work on PVA

Transdermal delivery system was prepared using polymers such as poly vinyl

alcohol (PVA), ethyl cellulose, Eudragit RL100, Eudragit L100 and Di‐n‐

butylphlthalate used as plasticizer. Metoprolol tartarate used as model drug,

system was developed to avoid bypass the hepatic first pass metabolism and

avoid drug degradation due to gastrointestinal pH, enzymes etc., also to

minimize plasma level fluctuations and extend the drug activity besides

improving patient compliance (Anilreddy et al., 2010). Mucoadhesive bilayered

buccal devices comprising of a methotrexate containing mucoadhesive layer and

drug free backing membrane was developed. Bi‐laminated patches composed of

mixture of drug (Methotrexate) and sodium alginate alone or in combination

with polyvinyl alcohol (PVA), sodium carboxymethyl cellulose, Polyvinyl

Pyrrolidone, Carbopol 934 and backing membrane (ethyl cellulose). The patches

were evaluated for In-vitro and Ex-vivo drug release, also evaluated for film

weight uniformity, thickness, swelling index, surface pH, mucoadhesive strength,

mucoadhesive time and folding endurance (Bhanja et al., 2010). Poly vinyl



alcohol, HPMC (15 & 47 cps), carbopol 934 & poly vinyl pyrolidone as polymer

and Pimozide used as model drug, for the preparation of buccal drug delivery

system (patches). The patches were evaluated for their thickness uniformity,

folding endurance, weight uniformity, content uniformity, swelling behaviour,

tensile strength, and surface pH. In vitro release studies of pimozide‐loaded

patches in phosphate buffer (pH, 6.6) exhibited drug release in the range of 55.32

% to 97.49 % in 60 min. Data of in vitro release from patches were fit in to

different equations and kinetic models to explain release kinetics (Basu et al.,

2010). Mucoadhesive buccal drug delivery system as films was developed for the

delivery of netrendipine. Mucoadhesive polymers like poly vinyl alcohol (PVA),

HPMC K‐100, sodium alginate and carbopol 934P were used. Prepared films

were characterised for content uniformity, radial swelling, surface pH, folding

endurance and in‐vitro drug release. The formulation containing 5% HPMC

showed best performance (Nappinnai et al., 2008). Poly vinyl alcohol (PVA),

HPMC (15 & 47 cps), chitosan and poly vinyl pyrrolidone were used to developed

buccal drug delivery system, and to increase the bioavailability and prevent first

pass metabolism of Resperidone. Mucoadhesive buccal patches of resperidone

may be good choice to bypass the extensive hepatic first pass metabolism with

an improvement in the bioavailability of resperidone through buccal mucosa

(Manasa et al., 2010). To avoid first pass hepatic metabolism mucoadhesive

buccal patches of Salbutamol sulphate were prepared, and evaluated the

developed patches for the physicochemical, mechanical and drug release

characteristics and found that the patches showed desired mechanical and

physicochemical properties to withstand environment of oral cavity. The patches

exhibited adequate stability when tested under accelerated conditions (Poddar

et al., 2009). Poly Vinyl Alcohol, Gelatin and Poly Sodium CMC were used for the

preparation of mucoadhesive buccal patch of aceclofenac. Patches were

evaluated for various parameters like weight variation, patch thickness, volume

entrapment efficiency %, and measurement of % elongation at break, folding

endurance, in vitro mucoadhesive time, in vitro release and stability study.

Among the eight formulations, formulation containing 4.5% gelatin showed

maximum desired properties release (Bhaviskar et al., 2009). Buccal patches of

felodipine were prepared to improve the bioavailability of the drug using poly



vinyl alcohol and poly vinyl pyrrolidone as polymer. To improve the flexibility of

the patch glycerol was used as plasticizer. In some cases the drug content was

decreases on storage for 6 months (Kulkarni et al., 2010). Mucoadhesive buccal

patches for delivery of cetylpyridinium chloride were developed using polyvinyl

alcohol (PVA), hydroxyethyl cellulose (HEC) and chitosan. The results showed a

remarkable increase in radial swelling after addition of the cetylpyridinium

chloride to the plain formulae. Physical characteristics of the studied patches

showed an increase in the residence time with storage accompanied with a

decrease in drug release (Ismail et al., 2003). The major hindrance for the

absorption of a drug taken orally was extensive first pass metabolism or stability

problems within the GI environment like instability in gastric pH and

complexation with mucosal membrane. These obstacles can be overcome by

altering the route of administration as parenteral, transdermal or transmucosal.

A number of mucoadhesive polymers like polyvinyl alcohol, HPMC and sodium

carboxy methyl cellulose were used for the preparation of transmucosal dosage

forms (Puratchikody et al., 2011).



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