6

CHAPTER II

LITERATURE ON CONTROLLED RELEASE

DRUG DELIVERY SYSTEMS

(MICROCAPSULES AND MATRIX TABLETS)

Controlled release drug delivery systems 1 are those dosage formulations

designed to release an active ingredient at rates, which differ significantly from

their corresponding conventional dosage forms. The controlled release drug

delivery systems are aimed at controlling the rate of drug delivery, sustaining the

duration of therapeutic activity and/or targeting the delivery of the drug to a tissue.

Drug release from these systems should be at a desired rate, predictable and

reproducible.

Controlled drug delivery occurs when a polymer, whether natural or

synthetic, is judiciously combined with a drug or active agent in such a way that

the active agent is released from the material in a predesigned manner. The release

of the active agent may be constant over a long period, it may be cyclic over a

long period, or it may be triggered by the environment or other external events.

Controlled release drug delivery systems provided one or more of the following

advantages.

1. Maintenance of optimum therapeutic drug concentration in the blood with

minimum fluctuations.

2. Predictable and reproducible release rates for extended duration.

7

3. Enhancement of therapeutic activity duration for drugs having short

biological half - life.

4. Elimination of side effects, frequent dosing and wastage of drugs.

5. Optimized therapy and better patient compliance.

6. To mask the unpleasant taste and odour of drugs.

7. Prevention of vaporization of volatile drugs.

8. Alteration of site of absorption.

9. Elimination of incompatibilities among the drugs.

The ideal drug delivery system should be inert, biocompatible,

mechanically strong, comfortable for the patient, capable of achieving high drug

loading, safe from accidental release, simple to administer and remove, and easy

to fabricate and sterilize.

In recent years, controlled drug delivery formulations and the polymers

used in these systems have become much more sophisticated, with the ability to

do more than simply extend the effective release period for a particular drug. For

example, current controlled-release systems can respond to changes in the

biological environment and deliver-or cease to deliver – drugs based on these

changes. In addition, materials have been developed that should lead to targeted

delivery systems, in which a particular formulation can be directed to the specific

cell, tissue or site where the drug it contains is to be delivered. While much of this

work is still in its early stages, emerging technologies offer possibilities that

scientists have only begun to explore.

8

2.1 ORAL CONTROLLED RELEASE SYSTEMS

The oral route is the most convenient and common mode for

administration of controlled release systems.

Oral route has been the most popular and successfully used for controlled

delivery of drugs because of convenience and ease of administration, greater

flexibility in dosage form design (possible because of versatility of g.i. anatomy

and physiology ) and ease of production and low cost of such a system. These

systems have gained importance because of the technological advances made in

fabrication, which help to achieve zero order release rates of therapeutic moiety.

The majority of oral controlled release systems rely on dissolution, diffusion or a

combination of both mechanisms to generate slow release of drug to the gastro-

intestinal milieu. Starting with limited data on a drug candidate for sustained

release, such as dose, rate constants for absorption and elimination, some elements

of metabolism and some physico-chemical properties of the drug, one can

estimate a desired release rate for the dosage form, the quantity of the drug

needed, and a preliminary strategy for the dosage form to be utilized. The

advantages of oral drug delivery systems are i) Reduced dosing frequency, ii)

Better patient convenience and compliance, iii) Reduced gastro-intestinal side

effects and toxic effects, iv) Less fluctuating plasma drug level, v) Most uniform

drug therapeutic effect, vi) Better stability of the drug.

The following are the major types of controlled release systems intended for

oral use.

9

1. Matrix tablets

Matrix tablets are monolithic systems in which drug is homogeneously

dispersed throughout a rate controlling medium. To control the release of the

drugs, hydrophobic and hydrophilic matrices have been used. For water soluble

drugs; the hydrophobic and hydrophilic matrices are mixed. For moderately or

poorly soluble drugs hydrophilic matrices are used. The drug dissolution is

controlled by controlling the rate of penetration of dissolution fluid in to the

matrix by altering the porosity of tablet, decreasing its wettability or by itself

getting dissolved at slower rate. The widely used hydrophobic and hydrophilic

materials for the preparation of matrix tablets are bees wax, hydrogenated castor

oil, hydroxy propyl methyl cellulose, xanthum gum and ethyl cellulose.

2. Mucoadhesive tablets

Mucoadhesive tablets are the controlled release drug delivery systems,

bind to the gastric epithelial cell surface or mucin and serve as a potential means

of extending the gastric retention time of drug delivery system in the stomach.

These systems prolong the intimacy and duration of contact of drug with the

biological membrane. Mucoadhesive polymers used in the preparation of tablets

utilize the property of adhesive interaction with a biological or gastrointestinal

mucosal surface. The characteristics of a mucoadhesive polymer are molecular

flexibility, hydrophilic functional groups, specific molecular weight, chain length

and conformation. These dosage forms are readily localized in the region applied

to enhance the bioavailability of drugs. These dosage forms facilitate intimate

contact of the formulation with the underlying absorption surface. This allows

modification of tissue permeability for absorption of drugs. Mucoadhesive

polymers are water insoluble and water soluble polymers, which form swellable

10

networks jointed by the cross linking agents. The commonly used polymers are

sodium carboxy methyl cellulose, carbopol, polycarbophil, sodium alginate,

hydroxy propyl methyl cellulose and gelatin.

The mucoadhesive drug delivery systems in the form of tablets, patches,

films and solutions have been developed for oral, buccal, vaginal, rectal and

ocular routes for enhancing bioavailability and for controlled release.

3. Microcapsules and microspheres

Microcapsules and microspheres are polymeric particles ranging in size

from 1-1000 µm. Microencapsulation is the process used to encase liquids, solids

and gases enclose within the polymeric embryonic membrane. The mechanism of

release is either by dissolution or diffusion of drug and the formulations are either

as encapsulated (microcapsules) or matrix (microspheres) form. Various methods

such as interfacial polymerization, coacervation-phase separation are used to

prepare microcapsules/microspheres. The thickness of the microcapsule coat can

be adjusted from 1 µm to 200 µm by changing the amount of coating material

applied from 3-30% of total weight. The coating material can be selected from a

wide variety of natural and synthetic polymers depending on the material to be

coated and the release characteristics desired. Microcapsules posses additional

advantage that sustained release of drug can be achieved with taste masking and

better g.i. tolerability.

11

4. Ion-exchange resins

The use of ion exchange resins is an attractive method for sustained drug

delivery. These types of systems are developed by embedding the drug molecules

in the ion-exchange resin matrix. In these systems drug release characteristics

largely depend only on the ionic environment of the resins containing drug. Ion

exchange based drug delivery systems are better suitable for drugs that are highly

susceptible to degradation by enzymatic processes. Ion exchange resins can be

divided into cation exchange resins and anion exchange resins. The most widely

used and safe ion-exchange resin is divinyl benzene sulphonate.

5. Film coated tablets

Coating of the tablets by using film forming polymers can control the

dissolution rate of drug from the tablets. Various polymers such as hydroxy propyl

methyl cellulose (HPMC), ethyl cellulose and eudragit have been used for the

polymeric film coating of the tablets. The polymer coatings act as diffusion

controlling mechanisms. By using both hydrophilic and hydrophobic polymers

one can accelerate the drug release. Thickness of the polymer coat is the important

parameter for the desired dissolution rate.

6. Floating tablets

Increased gastro intestinal transit time is the consequent property of

floating tablets. Floating tablets are used for local action in the proximal g.i. tract.

These systems are designed to have lesser specific gravity than the gastric

contents, thereby float on the gastro intestinal fluid for extended period. Poorly

soluble and unstable as well as poorly absorbable (in intestine) drugs are suitable

12

for floating dosage units. Hydrodynamically balanced systems are the typical

examples of floating tablets.

7. Swellable tablets

Swellable tablets are developed in a size, which can be swallowed and

when they reach stomach fluid, swell quickly and attain considerably larger size.

The dosage form is larger than the pylorus opening; it cannot pass through

pylorus, thereby, the residence time in stomach increases. The gastric emptying of

the swellable tablets is affected by their physical properties such as size, shape and

flexibility. In addition to the swelling, the gel forming property of the polymer can

retain the drug molecules within dosage form, there by sustaining the release of

drug from the formulations. Swellable tablets are prepared in various shapes such

as disk, string, pellet and tetrahedron. The tetrahedron shaped tablets showed an

increased residence time in stomach than tablets of other shapes. The commonly

used materials are gum karaya, guar gum, hydroxyl ethyl methacrylate and

polyethylene glycol.

8. Osmotic tablets

The osmotic tablets are comprised of a drug contained in a rigid, semi

permeable membrane in which an aperture (300 µm approx.) is created by a

mechanical drill or a laser beam. These systems are suitable for the controlled

release of water soluble drugs. The dispersion of drug molecules in the hydrogel

with in the tablet leads to controlled release. When water penetrates through the

semi-permeable membrane into the tablet mass by osmosis, osmotic pressure is

developed with in the tablet and as a result saturated solution of drug is forced out

of the tablet through the aperture. The two major factors, which control the

13

release, are the membrane permeability and the quality and quantity of hydrogel

polymer. Semi-permeable polymers such as cellulose acetate, ethyl carbamate,

polyamide and polyurethane are widely used.

9. Micro and multiple emulsions

Micro or sub-micron emulsions are having the dispersed phase diameter less

than 0.1µm and appear translucent or transparent and they are thermodynamically

stable compared to conventional emulsions. Multiple emulsions are containing

three phases either o/w/o or w/o/w type. The selection of type of emulsion

depends on the hydrophilic or lipophilic nature of the drugs. Lipid soluble drugs

are more suitable to these systems for improved absorption.

10. Electrically stimulated release devices2

These are monolithic devices prepared by using polyelectrolyte gels

which swell when an external electrical stimulus is applied, causing a change in

pH. The release could be modulated, by the current, giving a pulsatile release

profile.

11. Bioadhesive systems

Bioadhesive can be defined as any substance that can adhere to a

biological membrane and remain there for an extended period of time. If the

membrane substrate is then the polymer is referred to as mucoadhesive3. The

bioadhesives increase the residence time and contact time at the area of absorption

and provide a high concentration gradient across the membrane.

14

Among the various techniques, microencapsulation and matrix tablets have

been widely accepted for controlled release. In the present work

microencapsulation and matrix tablet by starch acetate and EVA was tried for

obtaining controlled release of glipizide. An overview of literature on

microencapsulation and matrix devices is given here.

2.2 MICROENCAPSULATION AND MICROCAPSULES

Microencapsulation may be defined as the process of surrounding or

enveloping one substance within another substance on a very small scale, yielding

capsules ranging from less than one micron to several hundred microns in size.

Microcapsules may be spherically shaped, with a continuous wall surrounding the

core, while others are asymmetrically and variably shaped, with a quantity of

smaller droplets of core material embedded throughout the microcapsule. Types of

microcapsules are shown in Fig. 2.1. All three states of matter (solids, liquids, and

gases) may be microencapsulated. This allows liquid and gas phase materials to be

handled more easily as solids, and can afford some measure of protection to those

handling hazardous materials.

Microencapsulation may be achieved by a myriad of techniques, with

several purposes in mind. Substances may be microencapsulated with the

intention that the core material be confined within capsule walls for a specific

period of time. Alternatively, core materials may be encapsulated so that the core

material will be released either gradually through the capsule walls, known as

controlled release or diffusion, or when external conditions trigger the capsule

walls to rupture, melt, or dissolve. The substance that is encapsulated may be

called the core material, the active ingredient or agent, fill, payload, nucleus, or

15

internal phase. The material encapsulating the core is referred to as the coating,

membrane, shell, or wall material. Microcapsules may have one wall or multiple

shells arranged in strata of varying thicknesses around the core.

Fig. 2.1: Various Types of Microcapsules

16

Applications:

There are almost limitless applications for microencapsulated material.

Microencapsulated materials are utilized in agriculture, pharmaceuticals, foods,

cosmetics and fragrances, textiles, paper, paints, coatings and adhesives, printing

applications, and many other industries.

Historically, carbonless copy paper was the first marketable product to

employ microcapsules. A coating of microencapsulated colorless ink is applied to

the top sheet of paper, and a developer is applied to the subsequent sheet. When

pressure is applied by writing, the capsules break and the ink reacts with the

developer to produce the dark color of the copy.

Today‟s textile industry makes use of microencapsulated materials to

enhance the properties of finished goods. One application increasingly utilized is

the incorporation of microencapsulated phase change materials (PCMs). Phase

change materials absorb and release heat in response to changes in environmental

temperatures. When temperatures rise, the phase change material melts, absorbing

excess heat, and feels cool. Conversely, as temperatures fall, the PCM releases

heat as it solidifies, and feels warm. This property of microencapsulated phase

change materials can be harnessed to increase the comfort level for users of sports

equipment, military gear, bedding, clothing, building materials, and many other

consumer products. Microencapsulated PCMs have even been used in NASA-

patented thermal protection systems for spacecraft.

Pesticides are encapsulated to be released over time, allowing farmers to

apply the pesticides less often rather than requiring very highly concentrated and

17

perhaps toxic initial applications followed by repeated applications to combat the

loss of efficacy due to leaching, evaporation and degradation. Protecting the

pesticides from full exposure to the elements lessens the risk to the environment

and those that might be exposed to the chemicals and provides a more efficient

strategy to pest control.

Ingredients in foods are encapsulated for several reasons. Most flavorings

are volatile; therefore encapsulation of these components extends the shelf-life of

products by retaining within the food flavors that would otherwise evaporate out

and be lost. Some ingredients are encapsulated to mask taste, such as nutrients

added to fortify a product without compromising the product‟s intended taste.

Alternatively, flavors are sometimes encapsulated to last longer, as in chewing

gum. The amount of encapsulated flavoring required is substantially less than

liquid flavoring, as liquid flavoring is lost and not recovered during chewing.

Flavorings that are comprised of two reactive components that, when encapsulated

individually, may be added to the finished product separately so that they do not

react and lose flavor potential prematurely. Some flavorings must also be

protected from oxidation or other reactions caused by exposure to light. Many

varieties of both oral and injected pharmaceutical formulations are

microencapsulated to release over longer periods of time or at certain locations in

the body. Aspirin, for example, can cause peptic ulcers and bleeding if doses are

introduced all at once. Therefore aspirin tablets are often produced by

compressing quantities of microcapsules that will gradually release the aspirin

through their shells, decreasing risk of stomach damage.

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Microencapsulation Processes:

Microencapsulation processes can be classified as follows4

I. Chemical processes

i) Interfacial polymerization

ii) In situ polymerization

iii) Orifice method

II. Physico-chemical processes

i) Coacervation - phase separation from aqueous solution

ii) Coacervation - phase separation in organic solution

iii) Complex coacervation

iv) Complex emulsion

v) Meltable dispersion

vi) Powder bed

III. Mechanical processes

i) Air suspension or fluidized bed coating

ii) Pan coating

iii) Spray - drying

iv) Spray - congealing

v) Electrostatic bonding

Microencapsulation processes are usually categorized into two groupings:

chemical processes and mechanical or physical processes. These labels can,

however, be somewhat misleading, as some processes classified as mechanical

might involve or even rely upon a chemical reaction, and some chemical

19

techniques rely solely on physical events. A clearer indication as to which

category an encapsulation method belongs is whether or not the capsules are

produced in a tank or reactor containing liquid, as in chemical processes, as

opposed to mechanical or physical processes, which employ a gas phase as part of

the encapsulation and rely chiefly on commercially available devices and

equipment to generate microcapsules.

Chemical Methods:

Capsules for carbonless paper and for many other applications are

produced by a chemical technique called complex coacervation. This method of

encapsulation takes advantages of the reaction of aqueous solutions of cationic

and anionic polymers such as gelatin and gum arabic. The polymers form a

concentrated phase called the complex coacervate. The coacervate exists in

equilibrium with a dilute supernatant phase. As water-immiscible core material is

introduced into the system, thin films of the polymer coacervate coat the dispersed

droplets of core material. The thin films are then solidified to make the capsules

harvestable.

Interfacial polymerization (IFP) is another chemical method of

microencapsulation. This technique is characterized by wall formation via the

rapid polymerization of monomers at the surface of the droplets or particles of

dispersed core material. A multifunctional monomer is dissolved in the core

material, and this solution is dispersed in an aqueous phase. A reactant to the

monomer is added to the aqueous phase, and polymerization quickly occurs at the

surfaces of the core droplets, forming the capsule walls. IFP can be used to

prepare bigger microcapsules, but most commercial IFP processes produce

20

smaller capsules in the 20-30 micron diameter range for herbicides and pesticide

uses, or even smaller 3-6 micron diameter range for carbonless paper ink.

Polymer-polymer incompatibility, also called phase separation, is

generally grouped with other chemical encapsulation techniques, despite the fact

that usually no actual chemical reaction is involved in the process. This method

utilizes two polymers that are soluble in a common solvent; yet do not mix with

one another in the solution. The polymers form two separate phases, one rich in

the polymer intended to form the capsule walls, the other rich in the incompatible

polymer meant to induce the separation of the two phases. The second polymer is

not intended to be part of the finished microcapsule wall, although some may be

caught inside the capsule shell and remain as an impurity.

In situ polymerization is a chemical encapsulation technique very similar

to interfacial polymerization. The distinguishing characteristic of in situ

polymerization is that no reactants are included in the core material. All

polymerization occurs in the continuous phase, rather than on both sides of the

interface between the continuous phase and the core material, as in IFP. Examples

of this method include urea-formaldehyde (UF) and melanine formaldehyde (MF)

encapsulation systems.

Centrifugal force processes were developed in the 1940s to encapsulate

fish oils and vitamins, protecting them from oxidation. In this method an oil and

water emulsion is extruded through small holes in a cup rotating within an oil

bath. The aqueous portion of the emulsion is rich in a water-soluble polymer, such

21

as gelatin, that gels when cooled. The resulting droplets are cooled to form gelled

polymer-matrix beads containing dispersed droplets of oil that are dried to isolate.

Similar in concept to centrifugal force processes, submerged nozzle

processes produce microcapsules when the oil core material is extruded with

gelatin through a two-fluid nozzle. The oil droplets are enveloped in gelatin as

they are extruded through the nozzle. Then the capsules are cooled to gel the

walls, before being collected and dried.

Physical Methods:

Spray drying is a mechanical microencapsulation method developed in the

1930‟s. An emulsion is prepared by dispersing the core material, usually an oil or

active ingredient immiscible with water; into a concentrated solution of wall

material until the desired size of oil droplets are attained. The resultant emulsion is

atomized into a spray of droplets by pumping the slurry through a rotating disc

into the heated compartment of a spray drier. There the water portion of the

emulsion is evaporated, yielding dried capsules of variable shape containing

scattered drops of core material. The capsules are collected through continuous

discharge from the spray drying chamber. This method can also be used to dry

small microencapsulated materials from aqueous slurry that are produced by

chemical methods.

Fluid bed coating, another mechanical encapsulation method, is restricted

to encapsulation of solid core materials, including liquids absorbed into porous

solids. This technique is used extensively to encapsulate pharmaceuticals. Solid

particles to be encapsulated are suspended on a jet of air and then covered by a

22

spray of liquid coating material. The capsules are then moved to an area where

their shells are solidified by cooling or solvent vaporization. The process of

suspending, spraying, and cooling is repeated until the capsules‟ walls are of the

desired thickness. This process is known as the Wurster process when the spray

nozzle is located at the bottom of the fluidized bed of particles. Both fluidized bed

coating and the Wurster process are variations of the pan coating method. In pan

coating, solid particles are mixed with a dry coating material and the temperature

is raised so that the coating material melts and encloses the core particles, and

then is solidified by cooling; or, the coating material can be gradually applied to

core particles tumbling in a vessel rather than being wholly mixed with the core

particles from the start of encapsulation.

Centrifugal extrusion processes generally produce capsules of a larger size,

from 250 microns up to a few millimeters in diameter. The core and the shell

materials, which should be immiscible with one another, are pushed through a

spinning two-fluid nozzle. This movement forms an unbroken rope which

naturally splits into round droplets directly after clearing the nozzle. The

continuous walls of these droplets are solidified either by cooling or by a gelling

bath, depending on the composition and properties of the coating material.

Another mechanical encapsulation process is rotational suspension

separation, or the spinning disk method. The internal phase is dispersed into the

liquid wall material and the mixture is advanced into a turning disk. Droplets of

pure shell material are thrown off the rim of the disk along with discrete particles

of core material enclosed in a skin of shell material. After having been solidified

23

by cooling, the microcapsules are collected separately from the particles of shell

material.

2.3 CONTROLLED RELEASE THROUGH MICROENCAPSULATION

Microencapsulation has been widely employed in the design of controlled

release dosage forms. The capsule shells can be designed to release their

ingredients at specific rate and/or under specific set of conditions.

Microencapsulation is perhaps the most widely accepted technique for oral and

parenteral controlled release. The use of microencapsulation for the production of

oral SR dosage forms has been widely employed in the last 50 years since the

successful introduction by Smith, Kline and French (SKF) in the early 1950s of

their „spansule‟ products. These products usually consist of large number of

microencapsules, having variable release rates because of the composition or

amount of the coating applied, filled into hard gelatin capsule shells. Upon

ingestion the outer shell quickly disintegrates in the stomach to liberate up to

1000-3000 microcapsules, which spread over the g.i. tract, thus ensuring more

reproducible drug absorption with less local irritation that occurs with many non-

disintegrating tablets designed for sustained release. Less frequently,

microcapsules are tabletted because of the risk of capsule rupture during

compression. Microcapsules have been formulated into suspensions having

controlled drug release properties.

Microencapsulation is the most promising technique for the design of

controlled release products for parenteral administration. The structure of the

microcapsules varies according to the process of preparation, but generally, there

24

are two distinctive types. The reservoir type possesses a central core of drug

coated with thin membrane of the polymer, whereas in the monolithic type (or

microspheres) the drug is dispersed homogeneously through out a polymeric

matrix. Polymers utilized for parenteral products must meet certain qualities

regarding their tissue compatibility, mechanical characteristics, drug permeability

and the specific property of being biodegradable (or bio-erodible).

The mechanism by which the active ingredient is released from the

microcapsules includes diffusion of the drug through the polymeric matrix, its

direct release through the pores of the polymer or as the polymeric material

erodes. In the case of reservoir microcapsules, the release rate is constant (i.e.

zero order rate), where as in monolithic microcapsules, the release rate generally

decreases with time.

A wide variety of medicaments were investigated for microencapsulation

majorly for obtaining sustained and controlled release. The medicaments studied

in the recent past (1995-2011) for oral controlled release include anti-infective

drugs (pyrimethamine5, isoniazid

6, norfloxacin

7,8, cephalexine

9, tetracycline

10),

analgesic and anti-inflammatory drugs (aspirin11

, indomethacin12,13

, ibuprofen14-18

,

diclofenac19-24

, naproxen25

, pentazocin26

, ketoprofen27-29

, apomorphine30

,

acetaminophen31

), anti-asthmatic and anti-allergic drugs (salbutamol32,33

,

theophylline34-39

, aminophylline40

), cardio-vascular drugs (nifedipine41-43

,

nicardipine44-45

, isosorbide dinitrate46

, captopril47

, diltiazem48

, propranolol49

) and

miscellaneous drugs such as lactobacilli50,51

(anti-diarrhoeal), chlorpromazine52

(anti-emetic), and cimetidine53

(anti-ulcer), chloroquine phosphate54

(anti-

malarial), isoxsuprene55

(uterine sedative), cephadrine56,57

(anti-microbial) and

25

sulphadiazine58

(anti-bacterial), doxifluridine59

, protein (bovine serum albumin60

),

gliclazide61

, tebuconazole62

, metronidazole63

, amifostine64

, vancomycin65,86

,

nifedipine66

, doxorubicin67

, insulin68

, clozapid69

, vitamin D270

, amoxicillin71,72

,

felodipine73

, alkannin74

, bupivacaine75

, lycopene76

, dexamethasone77

, verapamil78

,

atenolol79

, zidovudine80

, haloperidol81

, ethopropazine82

, thymopentin83

, isosorbide

dinitrate84

, tetracycline85

, zidovudine87

, celecoxib88

, melatonin89

, paclitaxel90

,

metformin91

, capreomycin sulfate92

, salbutamol93

, diltiazem hydrochloride94

,

lamivudine95

, clarithromycin96

and famotidine.97

Among the drugs that have been incorporated in microcapsules for

parenteral administration are steroids, especially contraceptives such as nor-

ethisterone and high molecular weight compounds such as peptides and proteins.

Water-soluble antibiotics with short half-lives such as ampicillin have also been

microencapsulated to achieve long acting therapeutic effect in an effort to prevent

infection and improve methods of treating wounds.

Research in microencapsulation has been receiving increasing attention for

controlled release and drug targeting. Many studies with biodegradable polymers

as coat materials were aimed at targeting. Polymers such as polylactide (PLA),

polyglycolide (PGA) and polyglactin 370 (PLGA) have been extensively studied

as microencapsulating materials.

Among the medicaments, biotechnology based protein drugs were

extensively investigated for controlled release and targeting through

microencapsulation. Biotechnology based drugs such as proteins as vaccine

adjuvants98

, β-glucuronidase recombinant hepatitis B antigen99

, hepatocytes100

,

26

recombinant human erythropoietin101

, nerve growth factor102

(NGF),

soneatropin103

, recombinant human interferon-gamma104

, immunoglobulin Y105

,

interleukin-2106

, transforming growth factor-beta (TGF-beta)107

, recombinant

human growth hormone (rhGH)108

and hormones109

like α-ovine leutinizing

hormone, β-human chorionic gonnadotropin, recombinant aminopeptidase

(PepN)110

interferon alpha-2B111

, DNA vaccine112

, ciliary Neurotrophic factor

(CNTF)113

and tetanus toxoid114,115

were microencapsulated and were

investigated.

Much research work on microencapsulation was carried out with known

coat materials such as gelatin, gelatin-acacia, ethyl cellulose, cellulose acetate

phthalate, shellac, eudragits (RS100, RL100), albumin, calcium alginate and poly

(DL-lactide). In a few studies new substances such as propylene glycol rosin

ester116

, abietic acid-sorbitol derivatives117

, cellulose acetate118-122

, poly(epsilon-

caprolactone)123

, hGH dextran124

, Alginate-cellulose sulphate-oligocation125

, ethyl

cellulose126

, poly (lactide-co-glycolide) (PLG)127

, poly(D,L-lactide-co-

glycolide)128

, gellan gum129

, olibanum resin130

, colophony131

, chitosan132

,

bharagum97

and polystyrene133

were evaluated as microencapsulating materials.

In the present study starch acetate, a new modified starch and EVA have

been evaluated as microencapsulating agents and to prepare starch acetate and

EVA coated microcapsules of glipizide for controlled release.

27

2.4 CONTROLLED RELEASE THROUGH MATRIX (MONOLITHIC)

DEVICES

Matrix (monolithic) devices are possibly the most common of the devices

for controlling the release of drugs. This is possibly because they are relatively

easy to fabricate, compared to reservoir devices, and there is not the danger of an

accidental high dosage that could result from the rupture of the membrane of a

reservoir device. In such a device the active agent is present as a dispersion within

the polymer matrix, and they are typically formed by the compression of a

polymer/drug mixture or by dissolution or melting. The dosage release properties

of monolithic devices may be dependent upon the solubility of the drug in the

polymer matrix or, in the case of porous matrices, the solubility in the sink

solution within the particle's pore network, and also the tortuosity of the

network134

(to a greater extent than the permeability of the film), dependent on

whether the drug is dispersed in the polymer or dissolved in the polymer. For low

loadings of drug, (0 to 5% w/v) the drug will be released by a solution-diffusion

mechanism (in the absence of pores). At higher loadings (5 to 10% w/v), the

release mechanism will be complicated by the presence of cavities formed near

the surface of the device as the drug is lost; such cavities fill with fluid from the

environment increasing the rate of release of the drug.

It is common to add a plasticizer (e.g. a poly ethylene glycol), or

surfactant, or adjuvant (i.e., an ingredient which increases effectiveness), to matrix

devices (and reservoir devices) as a means to enhance the permeability (although,

in contrast, plasticizer may be fugitive, and simply serve to aid film formation135

and, hence, decrease permeability - a property normally more desirable in polymer

28

paint coatings). It was noted that the leaching of PEG acted to increase the

permeability of (ethyl cellulose) films linearly as a function of PEG loading by

increasing the porosity, however, the films retained their barrier properties, not

permitting the transport of electrolyte136

. It was deduced that the enhancement of

their permeability was as a result of the effective decrease in thickness caused by

the PEG leaching. This was evidenced from plots of the cumulative permeant flux

per unit area as a function of time and film reciprocal thickness at a PEG loading

of 50% w/w plots showing a linear relationship between the rate of permeation

and reciprocal film thickness, as expected for a (Fickian) solution-diffusion type

transport mechanism in a homogeneous membrane. Extrapolation of the linear

regions of the graphs to the time axis gave positive intercepts on the time axis; the

magnitude of which decreased towards zero with decreasing film thickness. These

changing lag times were attributed to the occurrence of two diffusional flows

during the early stages of the experiment (the flow of the 'drug' and also the flow

of the PEG), and also to the more usual lag time during which the concentration of

permeant in the film is building-up.

Efentakis et al137

investigated the effects of added surfactants on

(hydrophobic) matrix devices. It was thought that surfactant may increase the drug

release rate by three possible mechanisms namely (i) Increased solubilization, (ii)

Improved „wettability‟ to the dissolution media and (iii) Pore formation as a result

of surfactant leaching.

For the system studied (Eudragit® RL 100 and RS 100 plasticized by

sorbitol, flurbiprofen as the drug, and a range of surfactants) it was concluded that

improved wetting of the tablet led to only a partial improvement in drug release

29

(implying that the release was diffusion, rather than dissolution, controlled),

although the effect was greater for Eudragit® RS than Eudragit

® RL, whilst the

greatest influence on release was by those surfactants that were more soluble due

to the formation of 'disruptions' in the matrix allowing the dissolution medium

access to within the matrix. This is of obvious relevance to a study of latex films

which might be suitable for pharmaceutical coatings, due to the ease with which a

polymer latex may be prepared with surfactant as opposed to surfactant-free.

Differences were found between the two polymers - with only the Eudragit®

RS

showing interactions between the anionic/cationic surfactant and drug. This was

ascribed to the differing levels of quaternary ammonium ions on the polymer.

Matrix properties of a new plant gum in controlled drug delivery were

investigated by V. D. Kalu et al.138

A new plant gum, Okra (extracted from the

pods of Hibiscus esculentus), has been evaluated as a controlled-release agent in

modified release matrices, in comparison with sodium carboxy methyl cellulose

(NaCMC) and hydroxy propyl methyl cellulose (HPMC), using paracetamol as a

model drug. Okra gum matrices provided a controlled-release of paracetamol for

more than 6h and the release rates followed time-independent kinetics. The release

rates were dependent on the concentration of the drug present in the matrix. The

addition of tablet excipients, lactose and Avicel, altered the dissolution profile and

the release kinetics. Okra gum compared favourably with Na CMC, and a

combination of Okra gum and Na CMC or on further addition of HPMC resulted

in near zero-order release of paracetamol from the matrix tablet.

Formulation of sustain release matrix systems of highly water soluble

drugs was investigated by S. Siddique et al.139

Matrix systems are of favour

30

because of their simplicity, patient compliance etc., than traditional drug delivery

which have many drawbacks like repeated administration, fluctuation in blood

concentration level etc. Developing oral sustained release matrix tablets for

highly water soluble drugs, if not formulated properly, may readily release the

drug at a faster rate, and are likely to produce toxic concentration of the drug on

oral administration. Hydrophilic polymer has become material of choice as an

important ingredient for formulating sustained release formulations of highly

water soluble drugs. Drug release to matrix system is determined by water

penetration, polymer swelling, drug dissolution, drug diffusion and matrix

erosion. Highly water soluble drugs like metoprolol tartrate, diltiazem, primodol,

ranitidine has been formulated as sustained release matrix tablets.

Drug release from matrix device:

Drug in the outside layer exposed to the bathing solution is dissolved first

and then diffuses out of the matrix. This process continues with the interface

between the bathing solution and solid drug moving toward the interior.

Obviously, for this system to be diffusion-controlled, the rate of dissolution of

drug particles within the matrix must be much faster than the diffusion rate of

dissolved drug leaving the matrix.

Fig. 2.2: Drug Delivery from a Typical Matrix Drug Delivery System

31

The equations, which describe the rate of release of drugs dispersed in an

inert matrix system have been derived by Higuchi140

. The following equation

can be written

dm/dh =d C0dh- Cs/2 ------ (1)

Where: dm = change in the amount of drug released per unit area.

dh = change in the thickness of the zone of matrix that has been depleted of drug.

Co = total amount of drug in a unit volume of the matrix.

Cs = saturated concentration of the drug within the matrix.

From the diffusion theory:

dm = Dm Cs/h dt ---------- (2)

where: Dm is the diffusion coefficient in the matrix.

Equating equations (1) and (2), integrating and solving for h gives

M = [Cs Dm (2Co-Cs)t]1/2

------(3)

when the amount of drug is in excess of the saturation concentration, that is

Co>>Cs

M = (2CsDmCot)1/2

-----------(4)

which indicates that the amount of drug released is a function of the square root of

time. In a similar manner, the drug release from a porous or granular matrix can

be described by

M= [DsC2 p/t (2co- pc

2]

1/2 ------(5)

where

p = porosity of the matrix

t = tortuosity

32

C2 = solubility of the drug in the release medium

Cs = diffusion coefficient in the release medium

This system is slightly different from the previous matrix system. In that

the drug is able to pass out of the matrix through fluid-filled channels and does not

pass through the polymer directly.

For purposes of data treatment, equation (4) or (5) can be reduced to

M = Kt1/2

where K is a constant.

So that a plot of amount of drug release versus the square root of time will

be linear, if the release of drug from the matrix is diffusion controlled. If this is

the case, then, by the Higuchi model, one may control the release of drug from a

homogeneous matrix system by varying141-145

initial concentration of drug in the

matrix, porosity, tortuosity, polymer system forming the matrix and solubility of

the drug.

In the present study starch acetate and EVA have been evaluated as release

retarding and rate – controlling polymer in matrix tablets for controlled release of

glipizide.

33

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