Modified Chitosan Drug Swelling

8/12/2019 Modified Chitosan Drug Swelling

1/89

DRUG RELEASE PROPERTIES OF CROSS-LINKED

N-CARBOXYMETHYLATED CHITOSAN WAFERS

(MINI DISSERTATION)

by

REFILWE MPHAHLELE

Submitted in partial fulfilment of the requirement for the degree

MASTER TECHNOLOGIAE PHARMACEUTICAL SCIENCES

In the

SCHOOL OF PHARMACY

FACULTY OF HEALTH SCIENCES

TSHWANE UNIVERSITY OF TECHNOLOGY

Supervisor: Prof. J.H. Hamman

Co-supervisor: Mr D. Nazer

2005


2/89

DECLARATION BY CANDITATE

I hereby declare that the mini dissertation submitted for the degree M. Tech: Pharmaceutical

Sciences, at Tshwane University of Technology, is my own original work and has not

previously been submitted to any other institution of higher education. I further declare that

all sources cited or quoted are indicated and acknowledged by means of a comprehensive list

of references.

Refilwe Mphahlele

CopyrightTshwane University of Technology


3/89

ACKNOWLEDGEMENTS

I would like to acknowledge the invaluable assistance and support that has enabled me to

proceed with this research from the following:

All The School of Pharmacy staff who have supported, helped and guided me throughout

this research. To Des and Sias, thanks a lot for including me in the chitosan team.

The Chemistry Department of Tshwane University of Technology, especially the

Garankuwa and Arcadia campuses; for their support, for availing materials and equipment.

Aventis Pharmaceuticals staff in Pretoriafor their support, time and equipment.

Mr N.F.H Makhubela for his assistance with the NMR spectrophotometer.

My loving familyspatience, assistance and support.


4/89

DEDICATION

In loving memory of my late parents, Christine and Joseph Morekhure.

Lord, thank you for the ethos and the strength.


5/89

TABLE OF CONTENTS

ABSTRACT ......................................................................................................................... 1

1 CHAPTER 1: Introduction ................................................................................... 3

1.1 Background and justification..................................................................................... 3

1.2 Chitosan..................................................................................................................... 3

1.3 Derivatives of chitosan .............................................................................................. 4

1.4 Modified drug release dosage forms ......................................................................... 5

1.5 Ibuprofen ................................................................................................................... 6

1.6 Research problem ...................................................................................................... 7

1.7 Hypothesis ................................................................................................................. 7

1.8 Aims and objectives .................................................................................................. 8

1.9 Study methods and design ......................................................................................... 8

2. CHAPTER 2: CHITOSAN AND DERIVATIVES.............................................. 9

2.1 Introduction ............................................................................................................... 9

2.2 Properties and applications of chitosan ..................................................................... 10

2.2.1 Physicochemical properties ....................................................................................... 11

2.2.2 Uses and applications of chitosan.............................................................................. 13

2.2.2.1 Controlled drug release systems................................................................................ 13

2.2.2.2 Drug targeting............................................................................................................ 14

i


6/89

2.2.2.3 Other applications...................................................................................................... 14

2.3 Derivatives of chitosan .............................................................................................. 15

2.3.1 N-Phthaloyl chitosan .................................................................................................16

2.3.2 N-trimethyl chitosan chloride (TMC)........................................................................ 17

2.3.2.1 Physicochemical properties ....................................................................................... 19

2.3.2.2 Absorption enhancing properties............................................................................... 19

2.3.3 Carboxymethyl chitosan (glycine glucan)................................................................. 20

2.3.3.1 Physicochemical properties ....................................................................................... 21

2.3.2.2 Absorption enhancing properties............................................................................... 21

2.4 Conclusion................................................................................................................. 23

3. CHAPTER 3: MODIFIED RELEASE DOSAGE FORMS ............................... 25

3.1 Introduction ............................................................................................................... 25

3.2 Nomenclature ............................................................................................................ 26

3.2.1 Delayed release.......................................................................................................... 26

3.2.2 Targeted release......................................................................................................... 27

3.2.3 Extended release dosage forms ................................................................................. 27

3.2.4 Repeat action ............................................................................................................. 27

3.2.5 Prolonged release....................................................................................................... 27

3.2.6 Sustained release ....................................................................................................... 27

3.2.7 Controlled release...................................................................................................... 27

ii


7/89

3.3 Design and function of modified release dosage forms ............................................ 28

3.3.1 Ideal properties of modified release dosage forms.................................................... 28

3.3.2 Types of modified release dosage forms ................................................................... 29

3.3.3 Selection of the type of dosage form......................................................................... 33

3.3.4 Mechanisms of drug release ...................................................................................... 33

3.3.5 Classification of modified release dosage forms....................................................... 34

3.3.5.1 Monolithic matrix delivery systems .......................................................................... 35

3.3.5.2 Reservoir or membrane-controlled systems .............................................................. 35

3.4 Chitosan as a drug carrier .......................................................................................... 36

3.4.1 Cross-linking of polymers to form matrices and/or hydrogels.................................. 37

3.4.2 Coating of dosage forms............................................................................................ 39

3.5 Conclusion................................................................................................................. 42

4. CHAPTER 4: N-CARBOXYMETHYL CHITOSAN PREPARATION AND

EVALUATION........................................................................................................... 43

4.1 Introduction ............................................................................................................... 43

4.2 Materials and equipment used ................................................................................... 43

4.3 Synthesis of N-Carboxymethyl chitosan ................................................................... 44

4.4 Characterisation of the synthesised N-carboxymethyl chitosan................................45

4.4.11H and

13C NMR characterisation ............................................................................. 52

4.4.2 Infrared (IR) characterisation .................................................................................... 55

iii


8/89

4.5 Cross-linking and wafer preparation ......................................................................... 56

4.6 Evaluation f N-carboxymethyl chitosan wafers ........................................................ 56

4.6.1 Drug content .............................................................................................................. 56

4.6.2 Swelling properties.................................................................................................... 58

4.6.3 Ibuprofen release tests at 60 rpm and 37C............................................................... 59

4.6.3.1 Dissolution profile at pH 5.8 ..................................................................................... 60



4.7 Data analysis.............................................................................................................. 65

4.7.1 Mean dissolution time ...............................................................................................65

4.7.2 Fit factors................................................................................................................... 67

4.8 Conclusion................................................................................................................. 68

5 Prospective studies ....................................................................................................69

BIBLIOGRAPHY 70

APPENDICES 76

iv


9/89

ABSTRACT

The delivery of drugs at the right time in a safe and reproducible manner to a specific target

at the required level has spurred the advancement of many innovative drug delivery system

technologies. These technologies for effective drug delivery include nanotechnology,

implants, microencapsulation, chemical modification as well as cell and peptide

encapsulation. The use of absorption enhancing polymers in bioadhesive drug formulations

to promote drug penetration through and between intestinal cells has been a subject of

various investigations.

Biodegradable, bioadhesive and biocompatible chitosan has emerged as a multifunctional

excipient that has been extensively explored for use in several modified release dosage forms

(MRDFs) including hydrogels, microspheres, wafers, beads/microgranules and transdermal

drug delivery systems. The advantage of most MRDFs is the elimination of the typical peak

and valley fluctuations in plasma drug concentration after repeated dosing with

conventional, immediate release dosage forms. Furthermore, protonated chitosan has been

reported to interact with components of the tight junctions, thereby enhancing paracellular

transportation of macromolecules across the gastrointestinal epithelium. An increased

residence time has been attributed to its bioadhesive nature. These extraordinary

characteristics are marred by the limited solubility of chitosan; hence the need to produce

derivatives with increased solubility over a wide pH range.

The primary amino groups in the chitosan polysaccharide impart chemical reactivity that

enables regioselective chemical modification. This results in the formation of various useful

derivatives including N-phthaloylated chitosan,N,N,N-trimethyl chitosan, N-carboxymethyl

chitosan and others. The use of cross-linked N-carboxymethyl chitosan wafers (or matrix

systems) was explored in this study for controlled release of the model drug, ibuprofen.

Theoretically, the added carboxyl (COOH) group should enhance its chelation properties,

which in turn are linked to its hydrogel formation properties. Barium chloride was used as

the cross-linker to ionically bind N-carboxymethyl chitosan chains to each other in order to

produce a hydrogel that was utilised to produce the wafers. The cross-linked N-

1


10/89

carboxymethyl chitosan was the only excipient used to make the hydrogel wafers thereby

reducing interference or erroneous deductions in the investigation.

The aim of this study was to investigate the hypothesis that drug release can be controlled by

wafers consisting of cross-linkedN-carboxymethyl chitosan in such a way that constant drug

quantities are released over an extended period of time. The drug release behaviour of the

cross-linked N-carboxymethyl chitosan wafers was evaluated in three different phosphate

buffers with pH values of 5.8, 7.4 and 8.0, respectively, to emulate the pH variation along the

gastrointestinal tract.

The results of this study demonstrated that the rate of ibuprofen release from the N-

carboxymethyl chitosan wafers was lower than its release from an immediate release dosage

form in the control group at all the pH values. However, the rate of ibuprofen release from

the wafers was higher in the slightly acidic environment (pH 5.8) as compared to the neutral

and alkaline environments. This higher release rate at a slightly acidic environment was

attributed to the excess protons (H+) that compete with the barium cation (Ba

2+) for

interacting with theN-carboxymethyl chitosan chains resulting in reversed cross-links with a

consequent faster erosion rate of the wafers at this pH value. This was confirmed by the

mass reduction of the wafers in the test for swelling properties.

The cross-linked N-carboxymethyl chitosan wafers showed potential as controlled release

dosage forms with higher mean dissolution time values as compared to the control group, but

different formulation aspects should be investigated in future studies to improve on the

performance of these wafers. Inclusion of binders and plasticisers to improve the mechanical

strength should be studied.

2


11/89

CHAPTER 1: INTRODUCTION

1.1 BACKGROUND AND JUSTIFICATION

The concentration of a drug in the blood fluctuates over successive administrations ofconventional single unit dosage forms. The main reason for this is because conventional

dosage forms are designed to release the complete dose of the drug immediately after

administration (i.e. burst release effect). This causes the drug blood concentration to rise to a

high value followed by a subsequent fall to a very low level as a result of elimination.

Forgotten doses or overnight no-dose periods may contribute further to this problem. These

fluctuating drug blood levels can be addressed by means of formulating dosage forms with

pre-determined drug release profiles. The ideal drug delivery system would keep the drug

blood plasma level constant over the treatment period after administration of a single dose

(Colett & Moreton, 2002).

These modified release dosage forms render invaluable therapeutic benefits such as reduced

frequency of drug administration, better patient compliance, improved control over the

maintenance of the plasma drug concentration, reduction in the severity and incidence of

localised gastrointestinal side effects as compared to conventional dosage forms as well as

cost saving because of better disease management (Colett & Moreton, 2002).

In this study, an attempt is made to formulate a controlled release drug delivery system in the

form of a cross-linkedN-carboxymethyl chitosan matrix system or wafer.

1.2 CHITOSAN

Chitosan is formed by partial deacetylation (40 - 98%) at theN-position of the linearpolymer

ofN-acetylglucosamine (i.e. chitin), which is found in crustacean shells and is also present in

some microorganisms and fungi such as yeasts. It is a linear amino polysaccharide made up

of copolymers ofN-acetyl-D-glucosamine and D-glucosamine. -1,4-gylcosidic bonds link-

up the sugar backbone to form (1-4)-2-amino-2-deoxy--D-glucan. The chemical structure

of a portion of the polymer chain is given in Figure 1.1. The absence of -glycosidase in the

3


12/89

upper part of the gastrointestinal tract implies that the -1,4-gylcosidic bond of chitosan will

only be degraded by bacterial -glycosidases in the lower part of the colon.

Figure 1.1: Chemical structure of a portion of a chitosan polymer chain (Kurita, 2001).

Chitosan is a bioadhesive, biocompatible, biodegradable, water insoluble, weak basic

polymer with a pKa of about 6.2 to 7.0, which means that it is insoluble in neutral and

alkaline media (Thanou, Verhoef & Junginger, 2001 and Hejazi & Amiji, 2003). Its

molecular mass ranges between 50 000 and 2 000 000 Da and it exists in a quasi-globular

conformation, which is stabilised by extensive intra- and intermolecular bonding. This is the

result of the highly reactive amino and hydroxyl groups, which contribute to the high

viscosity of chitosan solutions and also enhance chelation. It exhibits polymeric cationic

characteristics as well as gel and film-forming properties and enhances the rate of drug

absorption (Illum, 1998) with no indication of epithelial damage or cytotoxicity (Thanou,

Verhoef &Junginger, 2001).

Chitosan has various pharmaceutical uses such as a drug carrier, absorption enhancement,

controlled drug release, gene delivery, metal chelating agent, artificial skin, fungicide,

contact lens, weight loss aid, cholesterol lowering agent, burn dressings, clarification of

beverages and as a food supplement (Senel & McClure, 2004).

1.3 DERIVATIVES OF CHITOSAN

Derivatives of chitosan formed by N-substitution with carboxyl bearing groups showed

increased aqueous solubility and zwitterionic character. This allows for the formation of

clear gels at neutral and alkaline pH values but promotes aggregation in an acidic pH

environment (Thanou, Verhoef & Junginger, 2001). The aggregation behaviour led to the

4


13/89

need to cross-link the molecules to overcome cationisation of the amino groups and to

stabilise chitosan in acidic solutions.

Carboxymethyl chitosans are potentially multi-dentate ligands. Hejazi and Amiji (2003)

explained that these structural features render them potentially able to chelate metal ions like

Ca2+

, Ni2+

and Ba2+

,via the nitrogen lone pairs and the negative charge of the carboxylic

group to form stable complexes. Carboxymethyl chitosans aid with absorption by enhancing

paracellular transport through the controlled, transient and reversible opening of intestinal

tight junctions without being absorbed or interacting with charges of the lipid bilayer of the

cell membrane.

N-trimethyl chitosan chloride (TMC) is a soluble cationic methylated derivative of chitosan

(Le Dung et al.,1994), which can widen the paracellular route for the passage of hydrophilic

and macromolecular drugs after mucosal administration (Kotze et al.,1997 and Hamman et

al.,2003).

1.4 MODIFIED DRUG RELEASE DOSAGE FORMS

After oral administration of a conventional, immediate release dosage form, there is an

increase in the plasma drug concentration followed by an exponential decay. To achieve a

predetermined kinetic profile of plasma drug concentration it may be necessary to modify the

dosage form. An ideal modified release dosage form (MRDF) should be capable of releasing

a known amount of drug at a predetermined rate in order to produce an optimum therapeutic

effect. The most common advantage of modified release dosage forms is the elimination of

the typical peak and valley fluctuations in plasma drug concentration after repeated dosing

with conventional dosage forms (Lund, 1994).

There has been considerable interest in developing controlled or sustained drug delivery

systems using polymeric microspheres. Chitosan has attracted attention as a potential matrix

for use in controlled release dosage forms due to its favourable characteristics such as its

biodegradability and non-toxic nature (Thanoo, Sunny & Jayakrishnan, 1992). Cross-links

between polymer functional groups result in decreased hydrophilicity, thus slowing down the

rate of permeation of biological fluids throughout the matrix system. Consequently, the rate

5


14/89

of drug diffusion through the hydrated polymer also decreases. The use of complexation

between oppositely charged macromolecules to prepare chitosan beads as a controlled release

formulation for drugs is therefore a very useful way of modifying drug release (Shu & Zhu,

2000)

1.5 IBUPROFEN

The model drug, ibuprofen, is also known as 2-(4-isobutylphenyl)propionic acid and the

chemical structure is shown in Figure 1.2. Ibuprofen is a weakly acidic non-steroidal anti-

inflammatory drug that is slightly insoluble in water. A pKaof about 3.6 implies insolubility

in an acidic medium.

CHCOOH

CH3

CH2C

CH3

CH3 H

Figure 1.2: Chemical structure of ibuprofen or 2-(4-isobutylphenyl) propionic acid.

The biological half-life of 1.8 to 2 hours means that an oral dosage formulation of this drugwill be rapidly and almost completely absorbed from the gastrointestinal tract with peak

plasma concentrations occurring within 1-2 hours. The main adverse effects of ibuprofen are

gastrointestinal disturbances. In addition, poor solubility in water together with the short

plasma elimination half-life affect its bioavailability hence ibuprofens suitability for

modified release dosage forms. A wide therapeutic range or window of 1200 to 1800 mg/day

up to a maximum of 3200 mg/day allows formulation into controlled release dosage forms

with minimal risk of toxicity. Some of the therapeutic parameters mentioned above are

illustrated in Figure 1.3 (Martindale, 2002 and Ashford, 2002).

6


15/89

Figure 1.3: A plasma concentration-time curve illustrating the parameters associated with

the therapeutic or pharmacological response (Ashford, 2002)

1.6 RESEARCH PROBLEM

The drug dose is released immediately after administration of conventional dosage forms

with a quick rise in drug blood level and a subsequent decrease due to elimination. These

fluctuations may lead to toxic effects (at the peaks) or no therapeutic effect at all (at the

valleys). These typical peak and valley drug plasma levels may be overcome by

formulation of a modified release dosage form with predetermined drug release rate.

The question that needs to be answered in this study is: Can drug release be controlled by

wafers consisting of cross-linkedN-carboxymethyl chitosan in such a way to ensure constant

drug release over an extended period of time?

1.7 HYPOTHESIS

Drug release will be controlled by wafers consisting of cross-linked carboxymethyl chitosan

in such a way that constant drug quantities are released over an extended period of time.

7


16/89

1.8 AIMS AND OBJECTIVES

The aim of this investigation is to determine if the rate of ibuprofen release can be sustained

over an extended period by the formulation of cross-linked N-carboxymethyl chitosan

wafers. This will be supported by the following objectives:

The synthesis, infrared (IR) and nuclear magnetic resonance (NMR) characterisation

of the chitosan derivative,N-carboxymethyl chitosan,

The identification of an appropriate cation or ligand for the preparation of cross-

linkedN-carboxymethyl chitosan hydrogel to prepare wafers containing ibuprofen as

a model drug,

The evaluation of the drug release properties of the wafers by means of dissolutiontests at different pH values (representative of an acidic, neutral and alkaline

environment as in the gastrointestinal tract) and

Analysis of the dissolution profiles by calculating the mean dissolution time (MDT),

difference factor (f1) and similarity factor (f2).

1.9 STUDY METHODS AND DESIGN

This is a quantitative research study with a true experimental design where the dependent

variable (ibuprofen release) was manipulated (formation of cross-linked N-carboxymethyl

chitosan wafers) to measure the effect, but all other conditions were kept constant. Control

groups were included to indicate that the measured effect was indeed caused by the

manipulation and not by other external factors or chance interferences. The dissolution tests

were done in triplicate at different pH values and the results were reported with an analysis of

the dissolution curves in terms of the mean dissolution time (MDT) as well as the difference

(f1 ) and similarity factors (f2 ) for the efficient differentiation between overall release

patterns or the border line release profile differences.

8


17/89

CHAPTER 2: CHITOSAN AND CHITOSAN DERIVATIVES

2.1 INTRODUCTION

Chitosan is a cationic amino polysaccharide produced by the incomplete alkaline N-deacetylation of chitin, a naturally occurring nitrogeneous polysaccharide and supporting

material in the exoskeletons of crustaceans and insects. Chitin is structurally similar to

cellulose. The latter is a commonly used tablet excipient and has hydroxyl groups at the C-2

position in contrast to chitin which has acetamido groups [i.e. NH(C=O)CH3] at this position.

Chitosan has in addition to the acetamido groups also amino groups, NH2, at a certain

number of the C-2 positions as shown in Figure 2.1 (Kurita, 2001).

Chitosan has remarkable intrinsic properties such as biodegradability, bioadhesiveness

biocompatibility and drug absorption enhancement properties and has been used in drug

controlled release systems. Some of these unique characteristics are obscured by the limited

solubility of chitosan in more basic aqueous media similar to the intestines and the colon.

Consequently, this prompted extensive investigations to modify its structure and to

investigate pharmaceutical properties of various chitosan derivatives (Kurita, 2001).

Muzzarelli et al. (1982) demonstrated that N-carboxymethylation of chitosan could be

regioselectively synthesized using commercial grade reagents. Babak et al. (1999)

demonstrated that the surface activity of carboxymethyl chitin could be improved. A

separate study by Babak & Rinaudo (2002) confirmed the interaction between hydrosoluble

chitosan derivatives with surfactant to form surfacatant-polyelectrolyte complexes via

electrostatic and hydrophobic interactions.

A study by Kotz et al. (1997) and Hamman et al. (2003) revealed that the charge density

and the structural features of chitosan salts and N-trimethyl chitosan chloride (TMC) are

important factors that determine their potential use as absorption enhancers. Other TMC

studies by Kotz et al. (2002) demonstrated that TMC is an absorption enhancer over a wide

pH range and that TMC polymers with high degrees of quarternisation are less mucoadhesive

compared to those with lower degrees of quartenisation and this was attributed to changes in

9


18/89

the flexibility of the polymer chain. The same study revealed that TMC had no toxic effects.

According to Hamman & Kotze (2002), TMC reduced the transepithelial electrical resistance

(TEER) of Caco-2 cell monolayers in a slightly acidic environment (pH 6.2). TMC polymers

with higher degrees of quaternisation were found to have a higher number of positive charges

available for more electrostatic interactions between TMC and the cell membranes, resulting

in a greater number of tight junctions that are opened to allow for paracellular movement of

ions and thereby reduction of TEER.

2.2 PROPERTIES AND APPLICATIONS OF CHITOSAN

Chitosan refers to a large number of heteropolymers which differ in their degrees of N-

deacetylation (40 - 98%), viscosity grades and their molecular weights which vary between 2

000 Da for oligomers and 50 000 2 000 000 Da for polymers (Hejazi & Amiji, 2003). The

chemical structures of cellulose, chitin and chitosan including the synthetic step of partial

basicN-deacetylation of chitin to form chitosan are presented in Figure 2.1.

Figure 2.1: Comparison of the chemical structures of cellulose, chitin and chitosan

includingN-deacetylation of chitin to form chitosan (Kurita, 2001).

Figure 2.1 shows that chitosan is a polysaccharide made up of copolymers of N-acetyl-D-

glucosamine and D-glucosamine with a sugar backbone linked by -1,4 gylcosidic bonds to

form -(14) 2-amino-2-deoxy--D-glucan (Kurita, 2001). The glycosidic linkages of

chitosan are relatively stable against alkali but cleaved with acid and undergo total hydrolysis

10


19/89

with warm hydrochloric acid (HCl) to give the constituting monosaccharide, D-glucosamine

whilst mild acidic hydrolysis yields N-acetyl-D-glucosamine. In addition, the two hydroxyl

groups in the repeating hexosamine residue give rise to various novel biofunctional

hydrophobic macromolecular products with longer side chains. Enzymatic hydrolysis of

chitosan with lysozyme results in oligomer production whilst chitosanase from Bacillus sp.

gives dimer to pentamer products without producing the monomer. Enzymatic reactions that

occur in the lower part of the colon result in non-toxic degradation products (Kurita, 2001).

2.2.1 Physicochemical properties

Most naturally occurring polysaccharides like cellulose, dextran, pectin, alginic acid, agar,

agarose and carragenans are neutral or acidic in nature whereas chitosan is a weak base with

a pKavalue of about 6.2 - 7.0 and is therefore insoluble in neutral/aqueous and alkaline pH

media.

The presence of the amino group has a significant contribution to the characteristics of

chitosan as illustrated below:

The amine groups of chitosan are protonated in an acidic medium resulting in a

soluble polysaccharide with a relatively high charge density; one positive charge for

each D-glucosamine unit (Hejazi & Amiji, 2003).

Ravi Kumar, (2000) pointed out that due to the presence of the primary amino

groups, which are absent in cellulose, chitosan undergoes reactions typical of amines

with the most important ones beingthe Schiff reactions andN-acylation illustrated in

Figures 2.2 and 2.3, respectively.

Figure 2.2: Reaction of the free amino group of chitosan with an aldehyde to give the

corresponding Schiff base (Kurita, 2001).

11


20/89

Figure 2.3: Fully acylated chitosan at the amine and hydroxyl groups (Kurita, 2001).

Hejazi & Amiji (2003) stated that chitosan exists in a quasiglobular conformation

stabilised by extensive intra- and intermolecular hydrogen bonding as a result of the

highly reactive amino and hydroxyl groups, which also accounts for the high

viscosity of chitosan solutions. The amino groups also impart secondary amine

reactivity for modification reactions, which are not possible cellulose.

Chitosan forms hydrogels of which the swelling kinetics is affected by the extent of the

dissociation of the hydrogen bonds. They exhibit polymeric ionic characteristics and film

forming properties due to intermolecular hydrogen bonding (Illum, 1998; Thanou, Verhoef &

Junginger, 2001). Kurita, (2001) pointed out that chitosan is soluble in dilute solutions of

hydrochloric acid and aqueous organic acids such as formic acid, acetic acid, oxalic and

lactic acids and forms water-soluble salts with organic and inorganic acids such as glutamic

acid, acetic acid and hydrochloric acid. Chitosan with a low degree of deacetylation (i.e.

40%) is soluble up to a pH of 9, whereas highly deacetylated chitosan (i.e. 85%) is soluble

only up to a pH of 6.5. The latter has increased viscosity and an extended conformation with

a more flexible chain because of the charge repulsion in the molecule (Hejazi & Amiji,

2003). According to Senel & McClure, (2004) the high molecular weight of chitosan and a

linear unbranched structure make chitosan an excellent viscosity-enhancing agent in acidic

environments. It behaves as a pseudoplastic material exhibiting a decrease in viscosity with

increasing rates of shear. Kurita, (2001) explains that the degree of acetyl [NH(C=O)CH3]

substitution affects the adsorption of Cu(II). The adsorption capacities increase markedly in

the region of low substitution with increased hydrophilicity and decreases with further acetyl

substitution, which results in enhanced hydrophobicity.

12


21/89

2.2.2 Uses and applications of chitosan

Chitosans unique characteristics, low toxicity and FDA approval as a pharmaceutical

excipient (Muzzarelli, 1996) have increased its pharmaceutical applications and other uses as

indicated below.

2.2.2.1 Controlled drug release systems

Controlled drug release systems are designed to produce an optimum therapeutic response,

less side effects, prolonged efficacy, enhanced safety and reliability of drug therapy,

regulated drug release rate and reduced frequency of drug administration to encourage patient

compliance (Collet & Moreton, 2000). Chitosan has been utilised in several modified release

dosage forms as explained in the following examples.

pH-dependent chitosan hydrogels (Chen, Tian & Du, 2003), which are highly

swollen, hydrophilic polymer networks that can absorb large amounts of water and

drastically increase in volume depending on the molecular structure, gel structure,

degree of cross-linking, content and state of the water in the hydrogel (Yao et al.,

1998).

Chitosan tablets for controlled release as observed in anionic-cationic inter-polymer

networks (Mi et al., 1997). They reported alginate as an anionic polyelectrolyte to

control the swelling and erosion rates of chitosan tablets in acidic media.

Cross-linked chitosan microspheres for the controlled release of ibuprofen,

griseofulvin and aspirin (Arica et al., 2002 and Thanoo, Sunny & Jayakrishnan,

1992).

Controlled release studies by Gupta & Kumar, (1999) on diclofenac sodium release

from chitosan beads/microgranules and Arica et al. (2002) on sustained release of

ibuprofen from chitosan microspheres.

13


22/89

Transdermal drug delivery systems were designed using cross-linked chitosan

membranes to regulate propranolol release rate, which was found to depend on the

cross-link density within the membranes (Thacharodi & Rao, 1995).

2.2.2.2 Drug targeting

Chitosan can be used for drug release at specific sites, which include oral gene delivery

involving inhibition of DNA degradation facilitated by chitosan-DNA complexes, mucosal

vaccination, stomach-specific drug delivery, intestinal delivery and colon-specific delivery of

drugs (Hejazi et al.,2003).

2.2.2.3 Other applications

These are attributed to chitosans unique properties that promote its extensive use in industry

as outlined by Ravi Kumar, (2000) for various purposes such as

Removal of harmful metals for the detoxification of hazardous waste due to chitosans

versatility to adsorb metal ions and surfactants as well as chemical modification to

attract dyes and other moieties (Ravi Kumar, 2000),

Antacid and anti-ulcer characteristics which prevent drug irritation in the stomach and

thereby making chitosan a potentially suitable carrier in sustained drug delivery

systems (Gupta & Kumar, 2000 and Hou et al., 1985),

Antibacterial activity was demonstrated on the growth of E. coli and Fusarium

Alternaria attributed to the interaction of the chitosan C-2 cationic amino groups with

the anionic groups of the microorganisms (Hirano,1995),

Fat trapping involves the positively charged chitosan on the N-position binding free

fatty acids and bile components thereby retarding their absorption (Muzzarelli, 1999),

Photography involves the use of chitosans optical characteristics, film forming

ability, resistance to abrasion and fungicidal properties (Muzzarelli, 1997),

14


23/89

Opthalmology exploits chitosans optical clarity and correction, mechanical stability,

immunological compatibility to make contact lenses (Ravi Kumar, 2000),

Chromatography utilises the chiral field of chemically modified chitosan stationary

phase for asymmetric recognition and optical resolution of racemic mixtures (Senso,

Oliveros & Minguilln, 1999).

2.3 DERIVATIVES OF CHITOSAN

The pH-dependent solubility of chitosan presents a potential problem in the design and

formulation of sustained release dosage forms because of the variation in pH along the

gastrointestinal tract as presented in Figure 2.4. In addition, poor mechanical strength, the

quest for efficacy, safety and non-toxicity of chitosan controlled-release drug deliverysystems substantially influenced the course of chitosan research. This resulted in chemical

modifications by substitution at theN and/orO-position(s) to improve dissolution in various

media (Le Dung et al., 1994; Kurita, 1997; Thanou, Verhoef & Junginger, 2001; and Van der

Lubben et al., 2001).

Figure 2.4: pH variation along the gastrointestinal tract (Ashford, 2002).

15


24/89

The characteristic crystalline structure with intermolecular forces, limited solubility and

multifunctional nature of chitosan make chemical modifications difficult and necessitate

careful manipulation and proper control of the reactions such as the use of appropriate

regioselective reagents and reaction conditions which are mainly heterogeneous (Ravi

Kumar, 2000). Reactions with ketoacids followed by sodium borohydride reduction produce

glucans with proteic (e.g N-carboxymethyl chitosan) or non-proteic (e.g N-carboxybenzyl

chitosan) amino groups (Kurita, 2001 and Ravi Kumar, 2000). Different derivatives have

been explored together with trimethyl chitosan as absorption enhancers and for controlled

drug delivery by various researchers including Chen, Tian & Du, (2003), Thanou, Verhoef &

Junginger, (2001) and Babak et al, (1999) and Hamman & Kotze (2002).

2.3.1 N-Phthaloyl chitosan

N-Phthaloyl chitosan is formed by treating chitosan with excess phthalic anhydride at 120-

130oC to form both partial O- and fullyN-phthaloylated chitosan that is soluble in dimethyl

sulfoxide to protect the amino functionalities of the chitosan. Hydrazine can be used to

regenerate the free amino group(s) thereby providing a key intermediate to prepare

derivatives with well-defined structures under mild conditions and perfect discrimination of

functional groups for regioselectivity and quantitative viewpoints as illustrated in Figure 2.5.

Figure 2.5:Typical reactions to illustrate that the phthaloyl group is suitable for protection

of the amino group (Kurita, 2001 and Nishimura et al., 1991).

16


25/89

This derivative is also useful for solubilisation in organic solvents since the bulky phthaloyl

group prevents hydrogen bonding by eliminating hydrogens from the amino group (Kurita,

2001 and Nishimura et al., 1991). Other applications include the synthesis of non-natural

branched polysaccharides with potential biological functions such as immuno-adjuvant

activities and those with amino sugar branches, as shown in Figure 2.6, which have been

found to exhibit antimicrobial activity that is better than chitosan (Kurita et al., 2000).

Figure 2.6:Synthesis of polysaccharides with amino sugar branches by using an oxazoline

derived from N-acetylglucosamine to C-6 silylated OH acceptor in 1,2-

dichloroethane/camphorsulfonic acid at 80oC (Kurita, 2001 and Kurita et al, 1998).

2.3.2 N-trimethyl chitosan chloride (TMC)

Amines are Brnstead bases and hence are also nucleophiles that undergo bimolecular

nucleophilic substitution, SN2, reactions with alkyl halides to form alkylammonium ions.

Further alkylation may proceed if more N-H bonds are present as in amine quaternisation

(Loudon, 1995).

Exhaustive methylation of the primary amine of chitosan yields quaternary N-trimethyl

chitosan iodide as illustrated in Figure 2.7.

17


26/89

Figure 2.7: Preparation of a N,N,N-trimethyl chitosan iodide (monomer shown) by

methylation of chitosan (Thanou, Verhoef & Junginger, 2001).

According to Loudon (1995), alkyl substitution tends to stabilise the basicity of amines. This

can be explained by the fact that the alkyl groups exert a polarisation effect on the nitrogen

atom wherein the electron clouds of the alkyl group distort so as to create a net attraction

between them and the positive charge of the ammonium ion as illustrated in Figure 2.8.

Figure 2.8: Reinforcement of the basicity of an amine by quaternisation (Loudon, 1995).

Other known quaternary salts applied in the medical field are triton B and benzalkonium

chloride, a common antiseptic and a surfactant in water and is also soluble in organic

solvents (Loudon, 1995).

18


27/89

2.3.2.1 Physicochemical properties

N,N,N-trimethyl chitosan chloride is a fully ionic compound and has higher aqueous

solubility than chitosan in a much broader pH range, acidic to neutral media. This is

attributed to the fact that the alkyl groups tend to prevent hydrogen bond formation between

hydoxyl and amine groups of the chitosan backbone (Thanou, Verhoef and Junginger, 2001).

A study by Snyman et al. (2002) revealed that reductive alkylation results in an increase in

the molecular weight of the polymer due to the addition of methyl groups to the amino group

of the repeating monomers. The same study demonstrated that the intrinsic viscosity, as an

indication of the molecular weight, decreases with an increase in the degree of quaternisation

of the TMC polymers.

2.3.2.2 Absorption enhancing properties

The charge, charge density and the structural features of chitosan salts and N-trimethyl

chitosan chloride (TMC) are important factors which determine their potential use as

absorption enhancers for peptide drugs by reversibly interacting with components of the tight

junctions between epithelial cells and thereby widening paracellular routes for the passage of

hydrophilic and macromolecular drugs after mucosal administration (Kotze et al.,1997;

Hamman et al., 2001 and Van der Lubben et al., 2001).

A study by Thanou, Verhoef and Junginger, (2001) indicated that a threshold value of the

charge density of TMC is necessary to trigger the opening of the tight junctions at neutral pH

values. In addition, some studies revealed that the TMC polymer does not provoke cell

membrane damage on Caco-2 intestinal monolayers during enhancement of the transport of

hydrophilic macromolecules. This suggests that the mechanism of opening the tight

junctions is similar to that of protonated chitosan, that is, a specific interaction of the cationic

polymer with components of the tight junctions.

Figure 2.9 is an illustration of the junctional complexes between adjacent epithelial cells

including the tight junctions.

19


28/89

Figure 2.9: Tight junctions between adjacent epithelial cells.

Van der Lubben et al., (2001) indicated that the positive charge on TMC is only suitable for

improved delivery and absorption of hydrophilic, macromolecular drugs with neutral or basic

properties and thatN-substitution of chitosan with moieties bearing carboxyl groups, yielding

polyampholytic (zwitterionic) polymers is a promising approach, hence the investigation of

carboxymethyl chitosan as a drug absorption enhancer and a potential candidate for novel

drug delivery systems.

2.3.3 Carboxymethyl chitosan (glycine glucan)

Muzzarelli et al. (1982) pointed out that this N-carboxymethyl chitosan is a novel

polyampholyte, which may be prepared from a variety of chitosans differing in molecular

sizes, molecular-weight distributions, and degrees of deacetylation by treating them with

various amounts of glyoxylic acid. In addition, the N- and O-derivatives are chemically

different because the new group [NHCH2COOH] at the N-position is chemically similar to

glycine and hence raises interest in pharmaceutical chemistry. The lone pairs from the N-C-

C-O sequence of glycine contribute towards chelation properties superior to those exhibited

by tertiary amines of ethylene diammine tetraacetic acid (EDTA).

20


29/89

Carboxymethyl chitosan is synthesised by the reaction shown in Figure 2.10 and has amino,

glycine or acetamido groups at the C-2 position interspaced by glucose rings.

Figure 2.10: Formation of N-carboxymethyl chitosan from the reaction of chitosan with

glyoxylic acid followed by reduction with sodium borohydride (Thanou, Verhoef &

Junginger, 2001). MCC = monocarboxymethyl chitosan

2.3.3.1 Physicochemical properties

Thanou, (2001) observed that carboxymethyl chitosan with 87 - 90% degree of substitution

has polyampholytic (zwitterionic) character, which allows the formation of clear gels or

solutions depending on the polymer concentration at neutral and alkaline pH values but

aggregates under acidic conditions. Another significant characteristic is the complete

solubility ofN-carboxymethyl chitosan at all pH values.

2.3.3.2 Absorption enhancing properties

Robinson & Lee, (1997) noted that bioadhesive agents allow close contact of peptides to the

mucous lining, while at the same time minimising transit so that a high concentration

gradient across the membrane can be maintained for extended periods of time. This may

permit penetration enhancers and enzyme inhibitors to be used at lower concentrations

thereby lessening toxicity and irritation. This is achieved by the interaction of a number of

hydrophilic groups such as carboxyl (COOH), hydroxyl (OH), amide and sulfate (SO4)

groups. In addition, some bioadhesive agents have inherent penetration-enhancing effects

because they are effective ion chelators. These bioadhesive compounds can chelate calcium

ions (Ca2+

) in physiological buffers to affect the opening of tight junctions that is calcium

dependent. In view of the description of a bioadhesive and the structure and nature of

21


30/89

carboxymethyl chitosan, it seems to be a potential candidate for absorption enhancing

bioadhesives as it contains the carboxyl, hydroxyl and amide groups. They further highlight

the limitations associated with bioadhesive agents as:

Fouling of the bioadhesive sites of the polymer before reaching the desired target,

Rapid rate of mucus (or mucin) turnover making long-term adhesion impossible or too

slow to allow further passage of drug delivery system.

Thanou, Verhoef and Junginger, (2001) demonstrated that the polyanionic

monocarboxymethyl chitosan (MCC) concentration necessary to induce a 50% decrease in

transepithelial electrical resistance (TEER), an indication of opening of the tight junctions,

was several times higher than that of polycationic N,N,N-trimethyl chitosan chloride (TMC)at a neutral pH. In the same study, intra-duodenally administered MCC-bound Anti-Xa

serum and onset of absorption was delayed compared to when TMC was used. The delay

was attributed to the fact that MCC is unstable in acidic pH at the beginning of the duodenum

suggesting better absorption enhancing effect in intestinal medium.

As indicated under 2.2.2.1, a recent study by Di Colo et al., (2004) confirmed that

polyanionicN-carboxymethyl chitosan failed to enhance intraocular (pH 2) drug penetration

but increased precorneal ofloxacin retention due to its viscosity-increasing effect and

mucoadhesive binding to ofloxacin. The polyampholytic character favoured the formation of

clear gels or solutions through metal chelation and this depended on the concentration of the

polymer. The chitosan residue retained the protonated structure, which is essential for

enhancing paracellular drug absorption across the epithelial tight junctions even as

monocarboxymethyl chitosan.

Robinson & Lee, (1997) further advanced a concept of intelligent polymers, which refer to

soluble, surface-coated or cross-linked polymer systems that exhibit relatively large, sharp

physical or chemical changes in response to small physical or chemical stimuli such as

temperature, pH, solvent or electric field. They can change their properties rapidly according

to the environment. These polymers may be useful in the development of the next generation

of bioadhesive polymers that can target a drug to the desired site of absorption.

22


31/89

The results from studies by Thanou et al., (2001) and Di Colo et al., (2004) present a

problem for carboxymethyl chitosan use in the formulation of controlled drug release

delivery systems if linked to pH variations along the gastrointestinal tract. Muzzarelli et al.,

(1982) indicate that the chelation of metals by the carboxylate ion, -COO, of carboxymethyl

chitosan causes cross-linking of the polymer chains to yield swellable material or hydrogel in

pH dependent processes. The resultant reversible ionically-linked hydrogel is thought to be

significantly less cytotoxic than the hydrogel formed by glutaraldehyde (covalently-linked)

and is prepared in a simple and mild method for hydrogel formation. In addition, the

ionically cross-linked hydrogels seem to have more potential in the medical and

pharmaceutical fileds, since they are often biocompatible and have been investigated for

controlled drug delivery. Their disadvantages are the possible lack of mechanical stability

and the risk of dissolution of the system due to a highly pH-sensitive swelling (Berger et al.,

2004).

2.4 CONCLUSION

The production of chitosan from an abundant natural product, chitin, is done under moderate

conditions using simplified methods. Chitosan is a nitrogeneous polysaccharide with

favourable characteristics, but is insoluble at neutral and alkaline pH values. The remarkable

physicochemical properties of N-carboxymentyl chitosan, a chitosan derivative, including

complete aqueous solubility and the fact that it may be synthesised from commercial grade

reagents (Muzzarelli et al, 1982) make the exploration of cross-linked N-carboxymentyl

chitosan in various controlled drug release dosage forms an economically viable venture.

Moreover, the uses of chitosan and N-carboxymentyl chitosan in drug delivery have been

shown in several studies. Cross-linked chitosan has been shown to be a suitable matrix for

peroral microspheres for the controlled release of griseofulvin (Chithambara Thanoo, 1992;

Sunny & Jakakrishnan, 1992). Gupta & Kumar, (2000) demonstrated that the pH-dependent

pulsed release behaviour of glutaraldehyde and spacer group glycine cross-linked peroral

chitosan beads and microgranules could be altered by modifying the formulations to obtain

the desired controlled drug delivery systems. N-carboxymentyl chitosan has been found to

elicit negligible toxicity (Muzzarelli et al., 1982; Le Dung et al., 1994).

23


32/89

Previous studies to investigate nonparenteral routes of administration to overcome problems

like patient non-compliance with the parenteral route while maintaining therapeutic plasma

drug concentrations, have confirmed that N-carboxymentyl chitosan can be safely

administered via various routes including the ocular (Di Colo et al., 2004) and peroral route

(Thanou et al., 2001; Chen, Tian & Du, 2004).

The unique physicochemical properties of N-carboxymethyl chitosan suggest that this

chitosan derivative is a potentially viable candidate for various dosage forms including

controlled release dosage forms.

24


33/89

CHAPTER 3: MODIFIED RELEASE DOSAGE FORMS

3.1 INTRODUCTION

Various innovative technologies for effective drug delivery have been developed, includingimplants, nanotechnology, microencapsulation, chemical modification and others. This

development in technology was spurred by the quest to deliver drugs at the right time in a

safe and reproducible manner and to a specific target at the required concentrations.

Modified release drug formulations attempt to obtain zero-order release or a slow first-order

system to maintain required blood drug levels over extended periods. The drug delivery rate

is intended to balance the drug elimination rate as represented mathematically in Equation

3.1 (Jantzen & Robinson, 2002; Orive et al., 2003).

dde xVxCk limoutRateinRate == (3.1)

Cdis the desired drug level, Vdis the volume of distribution and kelimis the rate constant for

drug elimination. Figure 3.1 shows the pharmacokinetic patterns of a drug after the

administration of a conventional, controlled and sustained release dosage form, respectively.

Figure 3.1: Drug plasma-time profile of a zero-order controlled release, a slow-first-order

sustained release and a conventional dosage form (Jantzen & Robinson, 2002).

25


34/89

The advancement of drug delivery system development is influenced by physiological factors

such as the acidic conditions of the stomach, the first-pass effect of the liver and the intestinal

reduction of drug bioavailability. Physicochemical factors including aqueous solubility,

ionisation, pKa, dose size, partition coefficient and stability also had a significant role in the

course of modified release dosage form development. Moreover, over the years researchers

have managed to address several issues such as the need for suitable approved scientific

research, the impact of altered scientific policy on specific financial support, government

regulations and market forces present challenging barriers (Orive et al.,2003 and Jantzen &

Robinson, 2002).

3.2 NOMENCLATURE

Several literature sources such as Shargel and Yu, (1999) and Collet and Moreton, (2002)

acknowledge different terms to describe modified release dosage forms (MRDFs), which

include delayed release, extended release, repeat action, prolonged action, sustained release

and controlled release.

3.2.1 Delayed release

There is a release of discrete portion(s) of drug at a time(s) other than promptly after

administration although one portion may be released immediately after administration as a

loading dose. Common examples in this category are enteric-coated products such as

microspheres/beads in capsules (Shargel & Yu, 1999).

3.2.2 Targeted release

Drug release occurs at or near the intended physiologic site of action or site of absorption.

This may have either immediate or extended release characteristics as in nitroglycerine

sublingual tablets and transdermal patches (Transderm-Nitro

), respectively (Shargel & Yu,1999).

26


35/89

3.2.3 Extended release dosage forms

There is a slow drug release and plasma concentrations are maintained at a therapeutic level

for a prolonged period, usually between 8 and 12 hours (Collet & Moreton, 2002).

3.2.4 Repeat action

The first dose is released fairly soon after administration, the second or third doses are

subsequently released at intermittent intervals after administration of a single dosage form

(Collet & Moreton, 2002)

3.2.5 Prolonged release

The drug is provided for absorption over a longer period of time than that for a conventional

dosage form. Onset of action is thought to be delayed because of an overall slower release

rate from the dosage form (Collet & Moreton, 2002).

3.2.6 Sustained release

There is an initial release of drug sufficient to provide a therapeutic dose soon after

administration and then a gradual release over an extended period of time usually to try and

mimic zero-order release by providing a drug in a slow first-order manner (Jantzen &Robinson, Collet & Moreton, 2002).

3.2.7 Controlled release

The drug is released at a constant rate and provides plasma concentrations that remain

invariant with time (Collet & Moreton, 2002). This type of drug delivery system attempts to

control drug concentrations in the target tissue. The aim is to maintain therapeutic blood or

tissue drug levels constant over an extended period. This is usually accomplished by zero-

order drug release from the dosage form (Jantzen & Robinson, 2002).

27


36/89

3.3 DESIGN AND FUNCTION OF MODIFIED RELEASE DOSAGE FORMS

Several control mechanisms have been developed to achieve slow, controlled release of a

drug from tablets. These include drug transport by diffusion, dissolution, erosion, convective

flow accomplished by osmotic pumping and ion exchange control. Diffusion controlled and

dissolution controlled systems are the oldest, successful and most commonly used since they

are relatively easy and less expensive to manufacture (Alderborn, 2002 and Jantzen &

Robinson, 2002).

3.3.1 Ideal properties of a modified release dosage form

The ideal properties of a MRDF include the following (Shargel & Yu, 1999):

Efficacy and reduced or no toxicity, i.e. there should be no dose dumping or abrupt

release of a large amount of the drug. A single dose should show steady-state levels

within the therapeutic plasma levels comparable to those reached by using multiple

doses of a conventional dosage form as illustrated in Figure 3.2.

Figure 3.2: Plasma levels of a drug from a conventional tablet containing 50 mg of drug

administered at 0, 4 and 8 h in curve A compared to a single 150 mg drug dose given in an

extended release dosage form in curve B (Shargel & Yu, 1999).

28


37/89

Controlled drug release to control the therapeutic effect,

Consistent pharmacokinetic performance between individual dosage units to allow

for the maximum amount of drug to be absorbed,

Minimum patient-to-patient variation and better patient compliance,

Cost saving for treatment of patients, especially chronic conditions, even though the

cost of manufacture of a MRDF is generally higher than the cost of a conventional

dosage form,

3.3.2 Types of modified release dosage forms

Drug delivery system development has advanced extensively up to a point where there are

several simple and complex structured MRDFs already on the market. Most of the

characteristics outlined in 3.3.1 are satisfied, albeit the cost of manufacture is a hindrance for

most types of MRDFs. Shargel & Yu, (1999) describe various types of extended release

dosage form products as follows:

Pellet or bead type sustained release refer to beads prepared by coating drug powder

onto preformed cores called nonpareil seedswhich are made from slurry of starch,

sucrose and lactose. The drug beads, which may act as rapid-release carriers for the

drug, may be further coated with protective coating to allow a sustained or prolonged

release of the drug. Dissolution may also be controlled by variation in bead blending

or coating with different materials. The use of pH sensitive enteric coating materials

plus blending aid in providing two doses of a drug in one formulation which is ideal

for delivering the drug to the gastrointestinal tract regions with different pH values.

Prolonged-action tablets where drug release is controlled by altering the solubility so

that the tablet dissolves over a period of several hours. This is not easily

reproducible and therefore this dosage form is usually not reliable.

Ion-exchange applies in systems where the insoluble drug-resin complex dissociates

in the gastrointestinal tract in the presence of the appropriate counter ions. The

29


38/89

released drug then dissolves in the fluids of the gastrointestinal tract and is rapidly

absorbed. This dosage form is, however, not reliable because of uncontrollable

levels of counter ions and variability among individuals and resins may provide a

potential means of interaction with nutrients and other drugs.

A core tablet is a tablet within a tablet and is used as a slow drug-release component.

The outside shell contains a rapid-release dose of drug. The core material may be

surrounded by hydrophobic excipients so that the drug leaches out over a prolonged

period of time. This type of preparation is sometimes called slow erosion core tablet

because the core generally contains either no or insufficient disintegrant to fragment

the tablet. The composition of the core may range from waxy to gummy or

polymeric material.

Gum-type matrix tablet have a remarkable ability to swell in the presence of water to

form a gel-like consistency which provides a natural barrier to drug diffusion from

the tablet. The gel-like material is quite viscous and may not disperse for hours

thereby providing a means for sustaining the drug release over an extended period

until all the drug has been completely dissolved and has diffused into the intestinal

fluid. A common gel-forming material is gelatine. Modification of the release rates

of the product may further be achieved with various amounts of talc or other

lipophilic lubricant.

Micro encapsulation is a process of encapsulating microscopic drug particles with a

special coating material, thereby making the drug particles more desirable in terms of

physicochemical characteristics such as aspirin covered with ethylcellulose.

A polymeric matrix tablet involves the use of polymeric materials in prolonging the

release rate of a drug. Prolonged release may last for days and weeks rather than fora shorter duration as with other techniques. The first example of an oral polymeric

tablet is Gradumet

, which is marketed as an iron preparation. The plastic matrix

provides a rigid geometric surface for drug diffusion so that a relatively constant

drug release rate is obtained. In the case of the iron preparation, the matrix reduces

30


39/89

the exposure of the irritating drug to the gastrointestinal mucosal tissues. The matrix

is usually expelled unchanged in the faeces after all the drug has been leached out.

The matrix tablets for oral use are generally quite safe, however, for certain patients

with reduced gastrointestinal motility caused by disease, the polymeric matrix tablet

should be avoided. This is because obstruction of the gastrointestinal tract by the

matrix tablets has been reported. The use of the matrix tablet in implantation has

been more popular than orally administered products.

Osmotic controlled release is a fairly new concept in controlled-release preparations

where drug delivery is precisely controlled by the use of an osmotic controlled

device. It pumps a constant amount of water through the system dissolving and

releasing a constant amount of drug per unit time through the orifice. This device

consists of an outside layer of semi-permeable membrane filled with a mixture of

drug and osmotic agent. When the device is placed in water, osmotic pressure

generated by the osmotic agent within the core causes water to move into the device

through the membrane thereby forcing the dissolved drug to move out of the delivery

orifice. The process continues until all the drug is released. The rate of drug

delivery is relatively unaffected by the pH of the environment. The osmotic delivery

system has become a popular drug vehicle for many products that require extended

period of drug delivery for 12 to 24 hours some examples being Adalat CRand

Efidac 24. The osmotic preparation available for implantation is known as the

osmotic mini-pump.

Transdermal therapeutic systems (TTS) are intended for delivering a dose of

medication across the skin for systemic drug absorption. It can deliver the drug dose

through the skin in a controlled rate over an extended period of time. A semi-

permeable membrane next to the reservoir layer controls drug diffusion.

A monolith or matrix TTS has an occlusive backing layer to protect the drug matrix

which comprises a suspension of drug in equilibrium with its saturated solution for

maximum thermodynamic activity. The adhesive layer contains dissolved drug in

equilibrium with the matrix and attaches the patch to the skin (Barry, 2002).

31


40/89

Physicochemical and pharmacodynamic properties are the crucial criteria for the

choice of drug(s) suitable for TTS. Physicochemical properties of the drug include a

small molecular size (


41/89

increasing the proportion of the more hydrophilic polymer (e.g low molecular weight

polymer) thus increasing the rate of drug release. For example, the addition of polylactide to

a polylactide-polymer formulation increased the release rate of the drug and enabled the

preparation of a controlled-release system (Bodmeier et al., 1989).

Hydrophobic polymers with linkages susceptible to water hydrolysis are prepared so that

partial breakdown of the polymers allows for desired drug release without deforming the

matrix during erosion. For oral drug delivery, the problem of incomplete drug release from

the matrix is a major hurdle that must be overcome with polymeric matrix dosage forms.

Another problem is that the drug release rates may be affected by the amount of drug loaded.

For implantation and other uses, the environment is more stable, so that a stable drug release

from the polymer matrix may be attained for days or weeks.

3.3.3 Selection of the type of dosage form

The choice of the dosage form is an important factor in the delivery of the drug. It is

especially important to decide whether to formulate the active ingredient in:

A single unit system which includes tablets, coated tablets, matrix tablets or capsules,

A multiple unit system such as granules, beads, capsules or microcapsules (Collet &

Moreton, 2002).

The selection of the appropriate dosage form has to take in account an acceptable level of

variability of performance, the influence of gastrointestinal tract structure and function on the

delivery system, the release mechanism and release profile of the dosage form.

3.3.4 Mechanisms of drug release

Two basic drug release mechanisms are involved namely, dissolution of the active drug

component and the diffusion of dissolved or solubilised species out of the system into the

surrounding fluid. These mechanisms may operate independently, together or consecutively

and there are four processes operating within the context of these mechanisms, which include

(Collet & Moreton, 2002):

33


42/89

Hydration of the device (swelling of the hydrocolloid or dissolution of the

channelling agent),

Diffusion of water into the device,

Dissolution of the drug,

Diffusion of the dissolved (or solubilised) drug out of the device.

Drug release may be constant, declining or bimodal: In a constant release system the

modified release dosage form should provide and maintain constant drug plasma

concentrations, in other words, the system should exhibit zero-order kinetics. This led to

considerable effort being put into developing systems that release drugs at a constant rate.

A declining release system is commonly a function of the square root of time or follows first-

order kinetics. These systems cannot maintain a constant plasma drug concentration but can

provide sustained release. Bimodal release is based on the notion that the release rate must

always be slower than the absorption rate even if a constant drug release rate is achievable so

as to regulate drug absorption.

3.3.5 Classification of modified release dosage forms

The composition of MRDFs serves as a basis for their classification. Some components may

include active drug, release-controlling agent(s), matrix/membrane modifier, solubiliser, pH

modifier and/or density/modifier, lubricant and supplementary coatings in various

proportions (Collet & Moreton, 2002).

Alexandridis et al.(2000)point out that the composition of MRDF is channelled by certain

critical physicochemical considerations that include:

Efficient drug loading of the polymer-based delivery system,

Maintenance of the integrity of the drug during the loading process,

34


43/89

Proper surface properties of the drug delivery system, which promote the

biocompatibility, bioavailability and stability of the drug delivery system.

The kinetics and the mechanism of drug release from the carrier to the biological

system to achieve optimal drug release profiles.

3.3.5.1 Monolithic matrix delivery systems

Hydrophilic colloid matrices are systems where drug particles are dispersed in a soluble

matrix, in which the drug becomes available as the matrix dissolves or swells. Drugs

dispersed in a soluble matrix rely on a slow dissolution of the matrix to provide a sustained

release system. Alternatively, slowly dissolving fats and waxes undergo surface erosion with

little or no bulk erosion. If the matrix is presented with a conventional tablet geometry thesurface area of the matrix decreases with time with a concomitant decrease of drug release on

contact with the dissolution media (Collett & Moreton, 2002).

Hydrophobic lipid matrices and insoluble polymer matrices have drug particles dispersed in

an insoluble matrix and become available as the solvent enters the matrix and dissolves the

particles. Drug release from these matrices proceeds by way of penetration of fluid, followed

by dissolution of the drug particles and then diffusion through fluid-filled pores. This type of

delivery system would not be suitable for the release of compounds that are insoluble or

which have a low aqueous solubility. Excipients used in the preparation of insoluble

matrices include hydrophobic polymers, such as polyvinyl acetate, ethyl cellulose and some

waxes (Collett & Moreton, 2002).

3.3.5.2 Reservoir or membrane-controlled systems

A drug reservoir such as a tablet or multi-particulate pellet system is coated with a membrane

on the surface and not throughout the system as in the case of the matrix systems. The ratecontrolling part of the system is a membrane polymer through which the drug must diffuse

hence the membrane has to be permeable. The membrane neither swells nor erodes during

hydration. Membrane-controlled systems may occur as one of the following types (Collett &

Moreton, 2002):

35


44/89

Single unit systems: A film-coated tablet formulation where the core is not

allowed to disintegrate but to dissolve and water is allowed to penetrate the

membrane so that diffusion can occur.

Multiple unit systems: The system is made up of coated spheroids (pellets

approximately 1 mm in diameter) filled into a hard gelatin capsule or rarely

compressed into a tablet. The membrane coating is the critical part of the

formulation as it controls drug release.

Osmotic pump system: Drug is included in a tablet core which is water soluble

which will solubilise or suspend the drug in the presence of water. The tablet core

is coated with a semi-permeable membrane which allows the passage of water in

only, unlike in membrane systems where there is water in and drug out

movement. A hydrostatic pressure builds up and forces/pumps the drug

solution/suspension after the dissolution of the core through a hole (or orifice)

drilled in the coating after the dissolution of the core.

3.4 CHITOSAN AS A DRUG CARRIER

Chitosan is currently receiving a great deal of interest for medical and pharmaceutical

applications due to its favourable intrinsic properties such as biodegradability, bio-

adhesiveness and biocompatibility. The fact that derivatives can be formed to adapt to the

various physiological environments sparked interest in various studies such as the use of

chitosan nanoparticles and beads for controlled drug release (Thanoo, Sunny & Jayakrishnan,

1992; Gupta & Kumar, 2000).

The hydrophilic nature of chitosan and the varying pH regions of the gastrointestinal tract led

to chemical modifications of chitosan in an attempt to make it functional and effective in all

the regions. Examples include mono- and di-carboxymethylated chitosan for heparin

absorption (Thanou, Verhoef & Junginger, 2001) and mucoadhesive and absorption

enhancing properties of trimethyl chitosan chloride (Kotze et al.,2002).

36


45/89

3.4.1 Cross-linking of polymers to form matrices and/or hydrogels

Bodmeier, Chen & Paeratakul (1989) refer to cross-linking as the interaction of water-soluble

polymers bearing positively or negatively charged groups to form three-dimensional

networks with molecules of opposite charges, which may be used to entrap water-insoluble

drugs to facilitate their transport. The ionically cross-linkable polymers may be anionic or

cationic in nature and include but are not limited to carboxylic, sulfate, hydroxy and amine

functionalised polymers, normally referred to as hydrogels after being crosslinked. The term

"hydrogel" indicates a cross-linked, water insoluble, water-containing and swellable material

(Ronan & Thompson, 2001).

The cross-linking ions may be anions or cations depending on whether the polymer is

anionically or cationically cross-linkable. Appropriate cross-linking ions include calcium,

magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, cobalt, lead and

silver ions. Anions may be phosphate, citrate, borate, succinate, maleate, adipate and oxalate

ions. More broadly, the anions are derived from polybasic organic or inorganic acids. The

most preferred cross-linking cations are calcium and barium ions. The most preferred cross-

linking anion is phosphate. Cross-linking may be carried out by exposing the polymers to an

aqueous solution of the appropriate ions (Ronan & Thompson, 2001).

Suitable cross-linkable polymers include but are not limited to, one or a mixture of

polyethylene amine, alginic acid, carboxy methyl cellulose, hyaluronic acid, heparin sulfate,

chitosan, carboxymethyl chitosan, chitin, carboxymethyl starch, carboxymethyl dextra and

chondroitin sulfate. Polymers which are not ionically cross-linkable are used in blends with

polymers which are ionically cross-linkable (Ronan & Thompson, 2001).

Cross-linking may occur via irreversible covalent bonding to form a permanent network with

good mechanical properties, coordinate covalent bonding or ionic bonding to form hydrogels

that are more labile. Most of the cross-linkers used in covalent bonding tend to induce

toxicity if found in free traces before administration such as glutaraldehyde. This problem

may be overcome by reversible ionic cross-linking, which is a viable option for chitosan

because it can chelate with negatively charged ions via the protonated amine groups to form

37


46/89

a network through ionic bridges between polymeric chains. These can be characterised by

turbidimetric titration, viscometry or IR spectra (Berger et al., 2004).

Non-ionic cross-linking mechanisms have a higher cross-link density, improved mechanical

properties, i.e. improved stiffness, modulus, yield stress and strength. This may be

accomplished for the ionically cross-linkable polymer by additionally subjecting these to

non-ionic cross-linking mechanisms such as high-energy radiation (gamma rays) or treatment

with a chemical cross-linking agent reactive with groups present in the polymer such that

covalent bonds are formed connecting the polymer network. Another non-ionic cross-linking

mechanism useful with respect to some classes of hydrogel polymers is physical cross-

linking, which is typically accomplished by crystal formation or similar association of

polymer blocks such that the polymer molecules are physically tied together and prevented

from complete dissolution. Non-ionic cross-linking may be carried out prior to, subsequent

to or concurrently with ionic cross-linking (Ronan & Thompson, 2001).

One of the unique properties of polymer hydrogels is that the ionic cross-links can be easily

and selectively displaced in-vivoresulting in swelling and softening, which enhances patient

comfort. Since the non-ionic cross-links are not significantly displaced, the device will retain

its original non-ionically cross-linked shape configuration to a large degree and will not

disintegrate (Ronan & Thompson, 2001).

Berger et al., (2004) divided ionically cross-linked chitosan networks into two groups

depending on the type of cross-linker used, anions or anionic molecules, even though their

characteristics and properties are identical. They also emphasise that ionic cross-linking

requires multivalent counter-ions as cross-linkers to form bridges between polymeric chains.

According to this requirement, monovalent carboxymethylated chitosan is a potential

candidate for cross-linking with multivalent metals. Hejazi & Amiji, (2003) explained that

these structural features also render them potentially able to chelate metal ions with vacant d-

orbitals, like Co2+

and Zn2+

,via the nitrogen lone pairs and the negative charge of the

carboxylic group to form stable complexes. The mechanical strength of such neutral

complexes could aid with the controlled release of drugs.

38


47/89

3.4.2 Coating of dosage forms

Coating serves various purposes such as:

Masking of unpleasant taste,

Protection of components from atmospheric degradation,

Separation of reactive ingredients,

The control of the site for drug release as in enteric coating and

Delayed/prolonged absorption of the drug component by retarding drug release

from the dosage form (Hogan, 2002).

There are three major techniques for applying coatings to pharmaceutical solid dosage forms,

namely, sugar coating, compression coating and film coating. The latter comprises tablet

film coating and multi-particulate (micro-encapsulation) coating and performs the

pharmaceutical function of modifying drug release rate of some oral dosage forms (Hogan,

2002) and will therefore be described further.

Film coating is a more recently used technology in tablet coating and almost all newly

launched coated products are film coated (Hogan, 2002). This process involves the

deposition, usually by a spray method, of a thin, polymeric but uniform film onto the surface.

Initially highly volatile organic solvents were used but created many potential problems

including flammability, toxicity, concerns over environmental pollution, costs related to

minimising these problems plus the cost of the solvents themselves. The current film coating

methods rely more and more on water as the prime solvent. Film coating has proven to be a

popular alternative to sugar coating, because it allows additional substrates to be coated other

than just compressed tablets, for example, powders, granules, nonpareils and capsules

(Hogan, 2002).

Continuous spray techniques and manual application procedures have been used to coat a

moving bed of material. Film coating has proved successful as a result of the many

39


48/89

advantages offered which include minimal weight increase (typically only 2 to 3% of the

tablet core weight), significant reduction in processing times, increased process efficiency

and output because of improved in-process technology and equipment design, increased

flexibility in formulations and improved resistance to chipping of the coating (Hogan, 2002).

Raw materials used in film coating mainly consist of a polymer, plasticiser, colourant, and

solvent (or vehicle). Good interaction between solvent and polymer is necessary to ensure

that optimal film properties are obtained when the coating dries. This initial interaction

between solvent and polymer yields maximum polymer-chain extension, producing films

having the greatest cohesive strength and, thus, the best mechanical properties (Hogan,

2002).

The major solvents used in film coating typically belong to one of the following classes:

alcohols, ketones, esters, chlorinated hydrocarbons and water. An important function of the

solvent system is to ensure a controlled deposition of the coating material onto the surface of

the substrate so that a coherent and adherent film coat is obtained. Ideal properties for the

polymer include solubility in a wide range of solvent systems to promote flexibility in

formulation, an ability to produce coatings that have suitable mechanical properties and

appropriate solubility in gastrointestinal fluids such that drug bioavailability is not

compromised (Hogan, 2002).

Cellulose ethers are often the preferred polymers in film coating, particularly hydroxypropyl

methylcellulose. Suitable substitutes are hydroxypropyl cellulose, which may produce

slightly tackier coatings and methylcellulose, which is known to retard drug dissolution.

Alternatives to the cellulose ethers are certain acrylics, such as methacrylate and methyl

methacrylate copolymers, and vinyls such as polyvinyl alcohol (Hogan, 2002).

The incorporation of a plasticiser into the formulation improves the flexibility of the coating,

reduces the risk of the film cracking and possibly improves adhesion of the film to the

substrate. To ensure that these benefits are achieved, the platiciser must show a high degree

of compatibility with the polymer and be retained permanently in the film, if the properties of

the coating are to remain consistent on storage. Examples of typical plasticisers include

40


49/89

glycerin, propylene glycol, polyethylene glycol, triacetin, acetylated monoglyceride, citrate

esters (e.g. triethyl citrate) or phthalate esters (e.g. diethyl phthalate) (Hogan, 2002).

Functional coating, a modified form of film coating, confers controlled or enteric drug

release properties on dosage forms which such a

Modified Chitosan Drug Swelling

Documents

Transcript of Modified Chitosan Drug Swelling