Drug Delivery Systems a Review

Drug Delivery Systems:

A Review

Editor

A V Gothoskar

Dedicated to pharmacy profession

Acknowledgement:

SCES's Indira College of

Pharmacy, Pune

PREFACE

Men and medicine are inseparable from times immemorial. Although the physical forms of medication have not

changed dramatically, the attitude of the public toward accepting medicines have changed with the passage of time.

This fact is also reflected in the strategies adopted by the pharmaceutical companies in the field of research. The cost

involved, both in terms of time and money, has made it mandatory for the companies to reconsider their research

focus. In an attempt to reduce the cost of drug development process and advantageously reap the benefits of the

patent regime, drug delivery systems have become an integral part of the said process.

Drug delivery system is a dosage form, containing an element that exhibits temporal and/or spatial control over the

drug release. The ultimate aim of such systems is tailoring of the drug formulation to individual requirements under

the control of pathophysiological or in-vivo conditions rather than in-vitro characteristics.

This field of drug delivery systems is dynamic and extensive. Probably it would need an encyclopedia to cover all

the types of drug delivery systems. The aim of this book is to compile major drug delivery systems and offer a

source of information for all those working in pharmaceutical academia as well as industry.

The book is made available free of charge to all who are interested in the subject for dissemination of knowledge.

Authors feel proud to be a part of first of its kind of experiment wherein a technical book is offered for free

download through a blog.

We welcome suggestions and criticisms for our readers.

A V Gothoskar

PhD, MBA

Contributors

Bajaj Amruta Basrur Pooja Bhuruk Manisha

B.Pharm B.Pharm B.pharm, D.Pharm

Chavan Shankar Deshpande Tanvee Gothoskar Abhijit

B.Pharm B.Pharm PhD, MBA

Hastak Vishakha Kamble Pranay Katedeshmukh Ramesh

M.Pharm (Pharmaceutics) B.Pharm M.Pharm (Pharmaceutics)

Khan Halimunnisa Kulkarni Akshada Maravaniya Pathik Kumar

B.Pharm B.Pharm B.Pharm

Mogal Rajendra Patel Ruchita Pawar Sandesh M.Pharm (Pharmaceutics) B.Pharm B.Pharm, D.Pharm

Pawar Yogesh Satam Madhavi Sawant Sandip

M.Pharm (Pharmaceutics) B.Pharm B.Pharm

Shaikh Amir Shinde Rohit Suryavanshi Kiran

M.Pharm (Pharmaceutics) B.Pharm, D.Pharm B.Pharm, D.Pharm

Wayal Abhijit Zarikar Nitin

B.Pharm B.Pharm

Table of contents

1. Fundamentals of Drug Delivery System - 10

Suryavanshi Kiran, Mogal Rajendra, Pawar Yogesh, Shaikh Aamir

2. Oral Controlled Drug Delivery System - 18

Bajaj Amruta, Katedeshmukh Ramesh

3. Gastroretentive Drug Delivery System - 43

Basrur Pooja, Hastak Vishakha

4. Colon Specific Drug Delivery System - 59

Bhuruk Manisha, Pawar Yogesh

5. Chronopharmaceutical Drug Delivery System - 83

Chavan Shankar, Shaikh Aamir

6. Self Dispersing Formulations-101

Deshpande Tanvee, Mogal Rajendra

7. Introduction To Bioadhesion/Mucoadhesion - 114

Kamble Pranay, Katedeshmukh Ramesh

8. Mucoadhesive Drug Delivery System - Nasal - 127

Khan Halimunnisa, Hastak Vishakha

9. Mucoadhesive Drug Delivery System - Rectal - 149

Kulkarni Akshasa, Pawar Yogesh

10. Mucoadhesive Drug Delivery System - Vaginal - 160

Deshpande Tanvee, Shinde Rohit, Pawar Yogesh

11. Parenteral Controlled Drug Delivery System 182

Maravaniya Pathikkumar, Shaikh Aamir

12. Parenteral Implants 194

Patel Ruchita, Mogal Rajendra

13. Transdermal Drug Delivery System - 206

Pawar Sandesh, Katedeshmukh Ramesh

14. Particulate Drug Delivery System-Liposomes - 224

Satam Madhavi, Hastak Vishakha

15. Particulate Drug Delivery System- Microcapsules 241

Sawant Sandip, Pawar Yogesh

16. Particulate Drug Delivery System- Microspheres -253

Sawant Sandip, Pawar Yogesh

17. Particulate Drug Delivery System-Resealed Erythrocytes-266

Shinde Rohit, Shaikh Aamir

18. Particulate Drug Delivery System-Monoclonal Antibodies -281

Suryavanshi Kiran, Mogal Rajendra

19. Intranasal Drug Delivery System - 291

Wayal Abhijit, Katedeshmukh Ramesh

20. Protein And Peptide Drug Delivery System - 302

Zarikar Nitin, Hastak Vishakha

21. Intraocular Drug Delivery System - 318

Maravaniya Pathikkumar , Zarikar Nitin , Pawar Yogesh

22. Pulmonary Drug Delivery System 326

Kamble Pranay, Suryavanshi Kiran, Shaikh Aamir

23. Nanopharmaceuticals 334

Kulkarni Akshada, Patel Ruchita, Mogal Rajendra

24. Medicated Chewing Gums 347

Basrur Pooja, Katedeshmukh Ramesh

25. Oral Thin Film 357

Bhuruk Manisha, Satam Madhavi, Hastak Vishakha

26. Nail Drug Delivery System 367

Basrur Pooja, Suryavanshi Kiran, Katedeshmukh Ramesh

27. Regulatory Aspects of Drug Delivery System- 377

Chavan Shankar, Mogal Rajendra, Pawar Yogesh, Shaikh Aamir

Drug Delivery Systems - A Review

10

FUNDAMENTALS OF DRUG DELIVERY SYSTEMS Suryavanshi Kiran, Mogal Rajendra, Pawar Yogesh, Shaikh Aamir

Need for Controlled Release Systems:

(Kathryn E. Uhrich 1999)Controlled drug

delivery technology represents one of the most

rapidly advancing areas of science in which

chemists and chemical engineers are contributing to

human health care. Such delivery systems offer

numerous advantages compared to conventional

dosage forms including improved efficacy, reduced

toxicity, and improved patient compliance and

convenience. Such systems often use synthetic

polymers as carriers for the drugs. By so doing,

treatments that would not otherwise be possible are

now in conventional use. Although the introduction

of the first clinical controlled release systems

occurred less than 25 years ago, 1997 sales of

advanced drug delivery systems in the United

States alone were approximately $14 billion

dollars. Synthetic polymers used in the controlled

release of drugs. Before considering the variety and

the evolution of these polymeric structures, it is

necessary to examine the motivation for achieving

controlled release. This field of pharmaceutical

technology has grown and diversified rapidly in

recent years. Understanding the derivation of the

methods of controlled release and the range of new

polymers can be a barrier to involvement from the

nonspecialist. All controlled release systems aim to

improve the effectiveness of drug therapy. This

improvement can take the form of increasing

therapeutic activity compared to the intensity of

side effects, reducing the number of drug

administrations required during treatment, or

eliminating the need for specialized drug

administration (e.g., repeated injections).

B. Methods of Controlled Release

In temporal control, drug delivery systems aim to

deliver the drug over an extended duration or at as

specific time during treatment.

Controlled release over an extended duration is

highly beneficial for drugs that are rapidly

metabolized and eliminated from the body after

administration. An example of this benefit is shown

schematically in Figure 1 in which the

concentration of drug at the site of activity within

the body is compared after immediate release from

4 injections administered at 6 hourly intervals and

after extended release from a controlled release

system. Drug concentrations may fluctuate widely

during the 24 h period when the drug is

administered via bolus injection, and for only a

portion of the treatment period is the drug

concentration in the therapeutic window (i.e., the

drug concentration that produces beneficial effects

without harmful side effects). With the controlled

release system, the rate of drug release matches the

rate of drug elimination and, therefore, the drug

concentration is within the therapeutic window for

the vast majority of the 24 h period. Clinically,

temporal control can produce a significant

improvement in drug therapy. For example, when

an opioids pain killer is administered to a patient

with terminal cancer, any time that the drug

concentration is below therapeutic concentrations

the patient experiences pain. A temporally

controlled release system would ensure that the

maximum possible benefit is derived from the drug.

In distribution control, drug delivery systems aim

to target the release of the drug to the precise site of

activity within the body. The benefit of this type of

control is shown schematically in Figure 2 in which

Figure 1. Drug concentrations at site of

therapeutic action after delivery as a conventional

injection (thin line) and as a temporal controlled

release system (bold line). (Kathryn E. Uhrich

1999)


11

Figure 2. Drug delivery from an ideal distribution

controlled release system. Bold line: Drug

concentrations at site of therapeutic action. Thin

line: Systemic levels at which side effects occur.

(Kathryn E. Uhrich 1999)

Drug concentrations at the site of activity and side

effect production are compared. There are two

principle situations in which distribution control

can be beneficial. The first is when the natural

distribution causes drug molecules to encounter

tissues and cause major side effects that prohibit

further treatment. This situation is often the cause

of chemotherapy failure when bone marrow cell

death prevents the patient from undergoing a

complete drug treatment. The second situation is

when the natural distribution of the drug does not

allow drug molecules to reach their molecular site

of action. For example, a drug molecule that acts

on a receptor in the brain will not be active if it is

distributed by the patients blood system but cannot

cross the blood-brain barrier. A large number of

classes of drugs can benefit from temporal or

distribution controlled release. These classes

include chemotherapeutic drugs,

immunosuppressants, anti-inflammatory agents,

Antibiotics, opioid antagonists, steroids, hormones,

anesthetics, and vaccines. Recently, the need to

develop new controlled release strategies has been

intensified by advances in the design of peptide

drugs and emergence of gene therapy. These

biotechnology derived agents may dominate the

next generation of drug design. However, their

clinical success may be dependent on the design of

controlled release devices that ensure that the drugs

reach their target cells precisely at the required

time. A discussion of the pharmacological and

clinical motivations for controlling the release of

the specific drug classes referred to above is

beyond the limit of this article; however, a number

of excellent reviews are available. In addition, it

should be noted that controlled release technology

is not confined to pharmaceutical applications but

has also proven beneficial in agricultural and

cosmetic industries. (Kathryn E. Uhrich 1999)

Scope of Polymer Systems:

In this review, a number of polymer

backbones that are potentially degradable are

detailed in the text. This restriction certainly does

not reduce the impact and significance of C-C

backbones for controlled release applications but is

simply a mechanism to focus on an important

subset of materials. To illustrate the diverse range

of functionalities available from nonbiodegradable

systems based on C-C backbones to heteroatom-

containing polymer backbones that may confer

biodegradability. (Langer 1998)

Mechanisms of Controlled Drug Release Using

Polymers:

A diverse range of mechanisms have

been developed to achieve both temporal and

distribution controlled release of drugs using

polymers. This diversity is a necessary

consequence of different drugs imposing various

restrictions on the type of delivery system

employed. For example, a drug that is to be

released over an extended period in a patients

stomach where the pH is acidic and environmental

conditions fluctuate widely will require a controlled

release system very different from that of a drug

that is to be delivered in a pulsatile manner within

the blood system. An important consideration in

designing polymers for any controlled release

mechanism is the fate of the polymer after drug

release. Polymers that are naturally excreted from

the body are desirable for many controlled release

applications. These polymers may be excreted

directly via the kidneys or may be biodegraded into

smaller molecules that are then excreted.

Nondegradable polymers are acceptable in

applications in which the delivery system can be

recovered after drug release (e.g., removal of patch

or insert) or for oral applications in which the

polymer passes through the gastrointestinal tract.

From a polymer chemistry perspective, it is

important to appreciate that different mechanisms

of controlled release require polymers with a

variety of physicochemical properties. This

requirement has stimulated the evolution of the

new polymers that will be discussed in section IV.

Before consideration of these polymers, the major

mechanisms of controlled release and polymeric

characteristics that are required to carry out these

mechanisms will be briefly. (Kathryn E. Uhrich

1999)


12

CLASSIFICATION OF DRUG

DELIVERY SYSTEM:

Classification of NDDS based on Physical means

1) Osmotic Pressure Activated

2) Hydrodynamic pressure activated

3) Vapor pressure activated

4) Mechanically activated

5) Magnetically activated

6) Sonophoresis

7) Iontophoresis

8) Hydration activated

Classification of NDDS based on Chemical means

1) Hydrolysis activated

2) Ion activated

3) pH activated

Polymers Generally Used for Controlled Drug

Delivery System:

1) Poly(esters):

Poly (esters) is the best characterized and

most widely studied biodegradable system. The

synthesis of poly (esters) has received as much

attention as the degradation of these materials. A

patent for the use of poly (lactic acid) (PLA) as a

resorbable suture material was first filed in 1967.34

The mechanism of degradation in poly (ester)

materials is classified as bulk degradation with

random hydrolytic scission of the polymer

backbone

Polymerization of the cyclic lactone

alone is usually too slow to produce high molecular

weight material (>20 000 amu). The rate of ring

opening for the cyclic lactone can be increased by

activation of a Zn- or Snbased catalyst with the

carbonyl ester. However, the introduction of a

catalyst invites concerns over traces of potentially

cytotoxic material. Thus, stannous octoate SnII

(CO2CH(nBu)(Et))2 is commonly used because

has FDA approval as a food stabilizer.

Fig:3 Ring- opening polymerization of selected

cyclic lactones to give the following

A) Poly(e-caprolactone)PCL

B) Poly(glycolic acid) PGA

C) Poly(L-lactic acid)PLA (Kathryn E.

Uhrich 1999)

1. Poly(lactic acid), Poly(glycolic acid), and Their

Copolymers Poly(esters) based on poly(lactic acid)

(PLA), poly- (glycolic acid) (PGA), and their

copolymers, poly(lactic acid-co-glycolic acid)

(PLGA), are some of the best defined biomaterials

with regard to design and performance. Lactic acid

contains an asymmetric R-carbon which is typically

described as the D or L form in classical stereo

chemical terms and sometimes as the R and S form,

respectively. For homopolymers, the enantiomer

forms are poly (D-lactic acid) (PDLA) and poly (L-

lactic acid) (PLLA). The physicochemical

properties of optically active PDLA and PLLA are

nearly the same, whereas the racemic PLA has very

different characteristics.41 For example, racemic

PLA and PLLA have Tgs of 57 and 56 C,

respectively, but PLLA is highly crystalline with a

Tm of 170 C and racemic PLA is completely

amorphous.

Because the naturally occurring lactic acid

is L (or S), PLLA is considered more

biocompatible. The polymers are derived from

monomers that are natural metabolites of the body;

thus degradation of these materials yields the

corresponding hydroxy acid, making them safe for

in vivo use. Biocompatibility of the monomer is the

foundation for biocompatibility of degradable

polymer systems. To this end, the degradation

products often define the biocompatibility of a

polymers not necessarily the polymer itself. Even

though PLGA is extensively used and represents

the gold standard of degradable polymers,

increased local acidity due to the degradation can

lead to irritation at the site of the polymer


13

employment. Introduction of basic salts has been

investigated as a technique to control the pH in

local environment of PLGA implants

From a physical level of understanding,

poly (esters) undergo bulk degradation. PLA

homopolymers degrade slower than PGA

homopolymers on the basis of crystallinity as well

as stearic inhibition by the pendent methyl group of

PLA to hydrolytic attack. However, the complexity

of PLA, PGA, and PLGA degradation has been

demonstrated by Vert45 and does not conform to a

simple model. Vert and coworkers have

demonstrated that size dependence for hydrolytic

degradation exists for PLA systems. Other research

efforts suggest that PLA-derived micro particles

will degrade faster than nanoparticles derived from

PLA. This is modeled on diffusion reaction

phenomena. An autocatalytic effect at the interior

of larger devices is thought to contribute to the

initial heterogeneous degradation of larger devices

as acidic byproducts cannot readily diffuse out

from the interior as is the case for smaller

constructs. Extensive degradation studies have also

been reported for PLA, poly (caprolactone) (PCL),

and their copolymers both in vitro and in vivo.

Studies in hydrolytic degradation for poly (esters)

have focused on understanding the effects of

changes in polymer chain composition. A

distinguishable effect based on end group

composition for poly (ester) degradation

demonstrated that terminal carboxyl groups have a

catalytic effect on hydrolysis for PGA. The ability

to tailor rates of protein release from PLGA

microspheres was derived from the understanding

of end-group effects. The commercial

developmental process for formulating poly (esters)

with selected drug candidates has been reviewed.

The aforementioned review highlights the

development of poly (ester) matrices containing

human growth hormone that sustained levels of a

therapeutic protein in humans for 1 month from a

single dose. (Kathryn E. Uhrich 1999)

2. Poly (ethylene glycol) Block Copolymers:

Poly (ethylene glycol) (PEG) is also

referred to as poly (ethylene oxide) (PEO) at high

molecular weights. Biocompatibility is one of the

most noted advantages of this material. Typically,

PEG with molecular weights of 4000 amu is 98%

excreted in man. One of the emerging uses for

inclusion of PEG in a controlled release system

arises from its protein resistivity. The hydrophilic

nature of PEG is such that water hydrogen bonds

tightly with the polymer chain and thus excludes,

or inhibits, protein adsorption. Many research

groups are investigating attachment of PEG chains

to therapeutic proteins; PEG chains at the surface

allow for longer circulation of the protein in the

body by prolonging biological events such as

endocytosis, phagocytosis, liver uptake and

clearance, and other adsorptive processes.

Fig.4 Synthesis of PLA-PEG Copolymer (Kathryn

E. Uhrich 1999)

PEG can be made with a range of terminal

functionalities which lends to its easy incorporation

into copolymer systems. PEG is commonly

terminated with chain-end hydroxyl groups which

provide a ready handle for synthetic modification.

Diblock PLA/ PEG and triblock PLA/PEG/PLA

systems have been synthesized and characterized

with various PLA contents. The free hydroxyl

groups of PEG are ring-opening initiators for

lactide in forming the diblock or triblock materials

(Figure 5a, b). Recently, Chen et al. have

synthesized PLA-PEG multiblock copolymers from

L-lactide and ethylene oxide, the monomer

precursors for PLA and PEG, respectively (Figure

5c). This approach is different in two respects: (i)

use of bimetallic catalysts which proceed by

anionic mechanisms; (ii) multiblock polymers are

generated. Han and Hubbell further demonstrated

the synthetic utility for PLA-PEG systems by

introducing acrylate moieties to form cross-linked

systems. Similarly, Jeong et al. prepared thermo

sensitive PLA-PEO hydrogels that exhibit

temperature-dependent gel-sol transition for use as

injectable drug delivery systems.

Poly (ortho esters):

The motivation for designing poly (ortho

esters) for drug delivery was the need to develop

biodegradable polymers that inhibited drug release


14

by diffusion mechanisms and allowed drug release

only after the hydrolysis of polymer chains at the

surface of the device.70 Most research on poly

(ortho esters) has focused on the synthesis of

polymers by the addition of polyols to diketene

acetals. For example, Heller et al. have described

the synthesis and application of the 3, 9-

diethylidene-2, 4, 8, 10-tetraoxaspiro [5.5]

undecane (DETOSU)-based poly (ortho esters).71

The basic structure is formed by the addition of the

DETOSUmonomer to a diol to form the chemical

structure. The DETOSU-based poly (ortho esters)

contain acid labile ortho ester linkages in their

backbone structure. Within aqueous environments,

the ortho ester groups are hydrolyzed to form

Pentaerythritol dipropionate and diol monomers as

breakdown products. The Pentaerythritol

dipropionate is further hydrolyzed to

Pentaerythritol and acetic acid. Acid-catalyzed

hydrolysis of these polymers can be controlled by

introducing acidic or basic Excipients into

matrixes. Rates of hydrolysis can be increased by

the addition of acidic excipients, such as suberic

acid, as demonstrated by the zero-order release of

5-fluorouracil over a 15 day period.72

Alternatively, basic excipients stabilize the bulk of

the matrix but diffuse out of the surface region,

thereby facilitating surface-only erosion. This

approach has been employed in the temporal

controlled release of tetracycline over a period of

weeks in the treatment of periodontal disease.

Fig.5: Degradation of 3, 9(bis ethylidene-2, 4,8,10

Tetraoxaspiro undecane (DETOSU) based poly

ortho ester (Kathryn E. Uhrich 1999)

A useful feature of the DETOSU systems is

the ability to control the mechanical properties by

changing the diol monomer ratios within the final

polymeric structure. For example, Heller et al. have

shown that the glass transition temperature of

polymers containing a rigid diol monomer

(transcyclohexanedimethanol) and a flexible

monomer (1, 6- hexanediol) could be varied

between 20 and 105 by increasing the proportion

of the rigid diol. This control can also be achieved

with the glycolide containing polymers.

A number of applications have been

described for cross-linked poly (ortho esters)

formed by the substitution of 1, 2, 6-hexanetriol for

1, 2-hexanediol, for example. The triol monomer

allows cross-linked materials to be formed that are

semisolid materials. It has been envisaged that

these materials could be injected into the patient as

a viscous liquid at slightly elevated temperatures

that form nondeformable depot implants upon

cooling. (V. Balmurlidhara 2011)

Poly (anhydrides)

To obtain a device that erodes

heterogeneously, the polymer should be

hydrophobic yet contain water sensitive linkages.

One type of polymer system that meets this

requirement is the poly (anhydrides). Poly-

(anhydrides) undergoes hydrolytic bond cleavage

to form water-soluble degradation products that can

dissolve in an aqueous environment, thus resulting

in polymer erosion. Poly (anhydrides) are believed

to undergo predominantly surface erosion due to

the high water liability of the anhydride bonds on

the surface and the hydrophobicity which prevents

water penetration into the bulk. This process is

similar to the slow disappearance of a bar of soap

over time. The decrease in the device thickness

throughout the erosion process, maintenance of the

structural integrity, and the nearly zero-order

degradation kinetics suggest that heterogeneous

surface erosion predominates. The majority of poly

(anhydrides) are prepared by melt-condensation

polymerization. Starting with a dicarboxylic acid

monomer, a prepolymer of a mixed anhydride is

formed with acetic anhydride. The final polymer is

obtained by heating the prepolymer under vacuum

to remove the acetic anhydride byproduct. The

most widely studied poly (anhydrides) are based on

sebacic acid (SA), p-(carboxyphenoxy) propane

(CPP), and p-(carboxyphenoxy) hexane (CPH)

Degradation rates of these polymers can be

controlled by variations in polymer composition.

The more hydrophobic the monomer, the more

stable the anhydride bond is to hydrolysis.

Aliphatic poly- (anhydrides) (e.g., SA) degrade

within days whereas aromatic poly (anhydrides)

(e.g., CPH) degrade over several years.


15

Fig: 6 Structure of widely used aromatic poly

(anhydrides) based on monomer of p-carboxy

phenoxy propane (Kathryn E. Uhrich 1999)

The biocompatibility of copolymers of SA

and CPP has been well established. Evaluation of

the toxicity of poly (anhydrides) show that they

possess excellent in vivo biocompatibility.81

Recent clinical trials have demonstrated that an

intracranial device of SA/CPP copolymers

improves the therapeutic efficacy of an antitumor

agent, bischloronitrosourea, for patients suffering

from a lethal type of brain cancer.

Poly (anhydride-esters)

Other modifications of poly (anhydrides)

include poly (anhydride-esters), which include two

different types of hydrolytically cleavable bonds in

the polymer backbone. In one example, low

molecular weight carboxylic acid-terminated

prepolymer of poly (_- caprolactone) were coupled

via anhydride linkages. The intent of this research

was to design polymers that displayed two-stage

degradation profiles: anhydride bonds rapidly

hydrolyzed to the poly (ester) prepolymer which

degraded much more slowly. In another example,

carboxylic acid-terminated monomers that contain

ester bonds are activated and then polymerized

using the same chemistry described for the poly

(anhydrides). A unique aspect of these poly

(anhydride-esters) is that hydrolytic degradation of

the polymer backbone yields a therapeutically

useful compound, salicylic acid. Polymers

degradation products are potentially beneficial

Fig: 7 Poly (anhydride ester that undergo into

salicylic acid, an anti inflammatory agent (Kathryn

E. Uhrich 1999)

Poly (amides):

The most interesting class of poly

(amides) for controlled release are the poly (amino

acids). The synthetic ability to manipulate amino

acid sequences has seen its maturity over the last

two decades with new techniques and strategies

continually being introduced. An excellent review

of the histo4ry of amino acid-derived polymers is

given by Nathan and Kohn.93 Poly(amino acids)

have been used predominantly to deliver low

molecular weight drugs, are usually tolerated when

implanted in animals,94 and are metabolized to

relatively nontoxic products. These results suggest

good biocompatibility, but their mildly antigenic

nature makes their widespread use uncertain.

Another concern with poly (amino acids) is the

intrinsic hydrolytic stability of the amide bond

which must rely upon enzymes for bond cleavage.

The dependence on enzymes generally results in

poor controlled release in vivo. The expense and

difficulty in production of elaborate polypeptide

sequences has limited the composition to

homopolymers, predominantly poly (glutamic acid)

and poly (aspartic acid). Poly(amino acids) are

generally hydrophilic with degradation rates

dependent upon hydrophilicity of the amino

acids.96,97 Amino acids are attractive due to the

functionality they can provide a polymer. For

example, poly (lactic acid-co lysine) (PLAL) was

synthesized using a stannous octoate catalyst from

lactide and a lysine-containing monomer analogous

to lactide. Inclusion of the amino acid lysine

provides an amino group that allows for further

modification of the PLAL system. Recently,

peptide sequences that promote cell adhesion have

been attached to PLAL.


16

Fig.8 Poly (lactic acid-co-amino acid) PLAL

Polymer system (Kathryn E. Uhrich 1999)

Currently marketed oral controlled-release

systems:

Advances in oral controlled-release

technology are attributed to the development of

novel biocompatible polymers and machineries that

allow preparation of novel design dosage forms in a

reproducible manner. The main oral drug-delivery

approaches that have survived through the ages are

as follows:

Coating technology using various polymers for

coating tablets, nonpareil sugar beads, and granules

Matrix systems made of swell able or

nonswellable polymers

Slowly eroding devices

Osmotically controlled devices.

Conventional tablet formulations are still popular in

the design of single-unit, matrix-type controlled

release dosage forms. The advancement of

granulation technology and the array of polymers

available with various physicochemical properties

(such as modified cellulose or starch derivatives)

have made the development of novel oral

controlled release systems possible. Matrix devices

made with cellulose or acrylic acid derivatives,

which release the homogeneously dispersed drug

based on the penetration of water through the

matrix, have gained steady popularity because of

their simplicity in design. The drawback of matrix-

type delivery systems is their first-order drug

delivery mechanism caused by changing surface

area and drug diffusional path length with time.

This drawback has been addressed by osmotic

delivery systems, which maintain a zero-order drug

release irrespective of the pH and hydrodynamics

of the GI tract. Multiparticulate systems are gaining

favor over single-unit dosage forms because of

their desirable distribution characteristics,

reproducible transit time, and reduced chance of

gastric irritation owing to the localization of drug

delivery.

Although several technologies for the production of

microparticulate systems have been designed, thus

far the mainstream technologies are still based on

spray-drying, spheronization, and film-coating

technology.

FDA regulation of oral Controlled-

release drugs:

In the 1980s, FDA introduced rigorous

regulations governing bioequivalence and in vitro

in vivo correlations for controlled-release products.

Required pharmacokinetic evaluations involve

relative bioavailability following single dose

relative bioavailability following multiple doses

effect of food

dose proportionality

unit dosage strength proportionality

single-dose bioequivalence study

(Experimental versus marketed formulations at

various strengths)

In vivoin vitro correlation

Pharmacokinetic/pharmacodynamic (PK/PD)

relationship.

In general, for drugs in which the exposure

response relationship has not been established or is

unknown, applications for changing the

formulation from immediate release to controlled

release requires demonstration of the safety and

efficacy of the product in the target patient

population. When an NME is developed as a

controlled-release dosage form, additional studies

to characterize its absorption, distribution,

metabolism, and excretion (ADME) characteristics

are recommended.

The future of Drug Delivery System:

The future of controlled-release products

is promising, especially in the following areas that

present high promise and acceptability:

Particulate systems: The micro particle and

nanoparticle approach that involves biodegradable

polymers and is aimed at the uptake of intact drug-

loaded particles via the Peyers patches in the small

intestine could be useful for delivery of peptide

drugs that cannot, in general, be given orally.

Chronopharmacokinetic systems: Oral controlled

drug delivery with a pulsatile release regimen could

effectively deliver drugs where need exists to

counter naturally occurring processes such as

bacterial/parasitical growth patterns (e.g., the once-

daily oral Pulsys system introduced by Advancis

Pharmaceutical Corp., which could potentially

inhibit the emergence of resistant strains of

microorganisms).

Targeted drug delivery: Oral controlled drug

delivery that targets regions in the GI tract and


17

releases drugs only upon reaching that site could

offer effective treatment for certain disease states

(e.g. colon-targeted delivery of antineoplastics in

the treatment of colon cancer).

Mucoadhesive delivery: This is a promising

technique for buccal and sublingual drug delivery,

which can offer rapid onset of action and superior

bioavailability compared with simple oral delivery

because it bypasses firstpass metabolism in the

liver. (Das 2003)

Advantages of controlled drug delivery

systems:

1. Improved patient convenience and

compliance

2. Reduction in fluctuation in steady

state levels.

3. Increased safety margin of high

potency drugs.

4. Reduction in dose.

5. Reduction in health care cost.

Disadvantages of controlled drug

delivery systems:

1. Decreased systemic availability

2. Poor invitro-invivo correlations

3. Chances of dose dumping

4. Dose withdrawal is not possible.

5. Higher cost of formulation

Applications of controlled drug delivery

system:

1) Mucoadhesive drug delivery

system

2) Colon drug delivery system

3) Pulmonary drug delivery system

4) Ocular drug delivery system

5) Oral thin films

6) Nasal drug delivery system

7) Gastro retentive drug delivery

system

8) Vaginal drug delivery system

9) Resealed erythrocytes

References:

1. Www.Farmacist.Blogspot.Com.

2. Blanco Md, Alonso Mj. "Development

And Characterization Of ." Eur J. Pharma

Biopharm, 1997: 387-422.

3. Brouwers. "J. R. B. J." Pharm. World Sci,

1998.

4. Das, Nandita G. Das And Sudip K.

"Controlled-Release Of Oral Dosage

Forms." 2003: 10-16.

5. Kathryn E. Uhrich, Scott M. Cannizzaro

And Robert S. Langer,Kevin M.

Shakesheff. "Polymeric Systems For

Controlled Drug Release." 1999: 3181-

3198.

6. Katre, N. "Adv. Drug Delivery Review."

1993.

7. Langer, R. Nature 1998. 1998: 392.5.

8. Mehreganym, Gabriel KJ, Trimmer WSN.

1998: 35:719.

9. Paolino, Donatella. "Drug Delivery

System." Encyclopedia Of Medical

Devices And Instrumentation, 2006: 437-

485.

10. Ranade VV, Hollinger MA. "Drug

Delivery Systems." CRC Press, 1996.

11. Shivkumar, Vishal Gupta N. And.

"Development Of Drug Delivery System."

Trop J. Pharma, 2009.

12. Smith BR, Et Al. "A Biological

Perspective Of Particulate Nanoporous."

2004: 19-16.

13. V. Balmurlidhara, T.M. Pramodkumar.

"Ph Sensitive Drug Delivery System- A

Review." American Journal Of Drug

Delivery And Development, 2011: 24-48.


18

ORAL CONTROLLED DRUG DELIVERY SYSTEM Bajaj Amruta, Katedeshmukh Ramesh

Introduction:

Oral drug delivery is the most widely utilized route

of administration among all the routes [nasal,

ophthalmic, rectal, transdermal and Parenteral

routes] that have been explored for systemic

delivery of drugs via pharmaceutical products of

different dosage form. Oral route is considered

most natural, uncomplicated, convenient and safe

[in respect to Parenteral route] due to its ease of

administration, patient acceptance, and cost-

effective manufacturing process. Pharmaceutical

products designed for oral delivery are mainly

immediate release type or conventional drug

delivery systems, which are designed for

immediate release of drug for rapid absorption.

These immediate release dosage forms have some

limitations such as:

1) Drugs with short half-life requires frequent

administration, which increases chances of missing

dose of drug leading to poor patient compliance.

2) A typical peak-valley plasma concentration-time

profile is obtained which makes attainment of

steady state condition difficult.

3) The unavoidable fluctuations in the drug

concentration may lead to under medication or

overmedication as the CSS values fall or rise

beyond the therapeutic range.

4) The fluctuating drug levels may lead to

precipitation of adverse effects especially of a drug

with small therapeutic index, whenever

overmedication occurs.

In order to overcome the drawbacks of

conventional drug delivery systems, several

technical advancements have led to the

development of controlled drug delivery system

that could revolutionize method of medication and

provide a number of therapeutic benefits.

(Hemnani M. 2011)

TABLE 1:-Benefit Characteristics Of Oral Controlled-Release Drug Delivery System. (Das N. 2003)

Benefit Reason

Therapeutic advantage

Reduction in drug plasma level fluctuations;

maintenance of a steady plasma level of the drug over

a prolonged time period, ideally simulating an

intravenous infusion of a drug.

Reduction in adverse side effects and improvement in

tolerability

Drug plasma levels are maintained within a narrow

window with no sharp peaks and with AUC of plasma

concentration versus time curve comparable with total

AUC from multiple dosing with immediate release

dosage forms. This greatly reduces the possibility of

side effects, as the scale of side effects increase as we

approach the MSC.

Patient comfort and compliance

Oral drug delivery is the most common and

convenient for patients, and a reduction in dosing

frequency enhances compliance.

Reduction in healthcare cost

The total cost of therapy of the controlled release

product could be comparable or lower than the

immediate-release product. With reduction in side

effects, the overall expense in disease management

also would be reduced.

Controlled Drug Delivery Systems: (Hemnani M.

2011)

Controlled drug delivery systems have been

developed which are capable of controlling the rate

of drug delivery, sustaining the duration of

therapeutic activity and/or targeting the delivery of

drug to a tissue. Controlled drug delivery or

modified drug delivery systems are conveniently

divided into four categories.

1) Delayed release

2) Sustained release


19

3) Site-specific targeting

4) Receptor targeting

More precisely, controlled delivery can be defined

as:

1) Sustained drug action at a predetermined rate by

maintaining a relatively constant, effective drug

level in the body with concomitant minimization of

undesirable side effects.

2) Localized drug action by spatial placement of a

controlled release system adjacent to or in the

diseased tissue.

3) Targeted drug action by using carriers or

chemical derivatives to deliver drug to a particular

target cell type.

4) Provide a physiologically/therapeutically based

drug release system. In other words, the amount

and the rate of drug release are determined by the

physiological/ therapeutic needs of the body.

A controlled drug delivery system is usually

designed to deliver the drug at particular rate. Safe

and effective blood levels are maintained for a

period as long as the system continues to deliver

the drug. Controlled drug delivery usually results in

substantially constant blood levels of the active

ingredient as compared to the uncontrolled

fluctuations observed when multiple doses of quick

releasing conventional dosage forms are

administered to a patient.

Figure 1: A hypothetical plasma concentration-

time profile from conventional multiple dosing

and single doses of sustained and controlled

delivery formulations. Rationale of Controlled

Drug Delivery

The basic rationale for controlled drug delivery is

to alter the pharmacokinetics and

pharmacodynamics of pharmacologically active

moieties by using novel drug delivery system or by

modifying the molecular structure and/or

physiological parameters inherent in a selected

route of administration. It is desirable that the

duration of drug action become more a design

property of a rate controlled dosage form, and less,

or not at all, a property of the molecules inherent

kinetic properties. Thus optimal design of

controlled release systems necessitates a thorough

understanding of the pharmacokinetics and

pharmacodynamics of the drug. The primary

objectives of controlled drug delivery are to ensure

safety and to improve efficacy of drugs as well as

patient compliance. This is achieved by better

control of plasma drug levels and less frequent

dosing. The dose and dosing interval can be

modified in case of conventional dosage forms.

However, therapeutic window of plasma

concentration below which no therapeutic effect is

exhibited and above which undesirable effects are

manifested. Therapeutic index is the prime

parameter for development of a controlled delivery

system of a particular drug candidate.

Factors Affecting the Design and

Performance of Controlled Drug

Delivery: (Hemnani M. 2011)

1. Drug Properties:

Partition coefficient

Drug stability

Protein binding

Molecular size and diffusivity

2. Biological Properties:

Absorption

Metabolism

Elimination and biological half life

Dose size

Route of administration

Target sites

Acute or chronic therapy

Disease condition

Advantages of Controlled Drug Delivery

System: (Patel H. Nov Dec 2011):

1. Avoid patient compliance problems.

2. Employ less total drug

3. Minimize or eliminate local side effects

4. Minimize or eliminate systemic side

effects

5. Obtain less potentiating or reduction in

drug activity with chronic use.

6. Minimize drug accumulation with

chronic dosing.


20

7. Improve efficiency in treatment

8. Cures or controls condition more

promptly.

9. Improves control of condition i.e.,

reduced fluctuation in drug level.

10. Improves bioavailability of some drugs.

11. Make use of special effects, E.g.

Sustained-release aspirin for morning

relief of arthritis by dosing before bed

time.

12. Economy i.e. reduction in health care

costs. The average cost of treatment over

an extended time period may be less, with

less frequency of dosing, enhanced

therapeutic benefits and reduced side

effects.

13. The time required for health care

personnel to dispense and administer the

drug and monitor patient is also reduced.

Disadvantages: (Kamboj S 2009)

1) Decreased systemic availability in

comparison to immediate release

conventional dosage forms, which may be

due to incomplete release, increased first-

pass metabolism, increased instability,

insufficient residence time for complete

release, site specific absorption, pH

dependent stability etc.

2) Poor in vitro in vivo correlation.

3) Possibility of dose dumping due to food,

physiologic or formulation variables or

chewing or grinding of oral formulations

by the patient and thus, increased risk of

toxicity.

4) Retrieval of drug is difficult in case of

toxicity, poisoning or hypersensitivity

reactions.

5) Reduced potential for dosage adjustment

of drugs normally administered in varying

strengths.

6) Stability problems.

7) Increased cost.

8) More rapid development of tolerance and

counseling.

9) Need for additional patient education and

counseling

Oral Controlled Drug Delivery Systems:

(Hemnani M. 2011)

Oral controlled release drug delivery is a drug

delivery system that provides the continuous oral

delivery of drugs at predictable and reproducible

kinetics for a predetermined period throughout the

course of GI transit and also the system that target

the delivery of a drug to a specific region within the

GI tract for either a local or systemic action.

All the pharmaceutical products formulated for

systemic delivery via the oral route of

administration, irrespective of the mode of delivery

(immediate, sustained or controlled release) and the

design of dosage form (either solid dispersion or

liquid), must be developed within the intrinsic

characteristics of GI physiology. Therefore the

scientific framework required for the successful

development of oral drug delivery systems consists

of basic understanding of

(i) physicochemical, pharmacokinetic

and pharmacodynamic characteristics

of the drug

(ii) the anatomic and physiologic

characteristics of the gastrointestinal

tract

(iii) physicochemical characteristics and

the drug delivery mode of the dosage

form to be designed.

The main areas of potential challenge in the

development of oral controlled drug delivery

systems are:-

1) Development of a drug delivery system: To

develop a viable oral controlled release drug

delivery system capable of delivering a drug at a

therapeutically effective rate to a desirable site for

duration required for optimal treatment.

2) Modulation of gastrointestinal transit time: To

modulate the GI transit time so that the drug

delivery system developed can be transported to a

target site or to the vicinity of an absorption site

and reside there for a prolonged period of time to

maximize the delivery of a drug dose.

3) Minimization of hepatic first pass elimination: If

the drug to be delivered is subjected to extensive

hepatic first-pass elimination, preventive measures

should be devised to either bypass or minimize the

extent of hepatic metabolic effect.


21

Methods Used To Achieve Controlled Release

Of Orally Administered Drugs:

A. Diffusion Controlled System:

Basically diffusion process shows the movement of

drug molecules from a region of a higher

concentration to one of lower concentration.

This system is of two types:

a) Reservoir type: A core of drug surrounded by

polymer membrane, which controls the release rate,

characterizes reservoir devices.

b) Matrix type: Matrix system is characterized by

a homogenous dispersion of solid drug in a

polymer mixture.

B. Dissolution Controlled Systems:

a) Reservoir type: Drug is coated with a given

thickness coating, which is slowly dissolved in the

contents of gastrointestinal tract. By alternating

layers of drug with the rate controlling coats as

shown in figure no.2, a pulsed delivery can be

achieved. If the outer layer is quickly releasing

bolus dose of the drug, initial levels of the drug in

the body can be quickly established with pulsed

intervals

Figure 2: Schematic representation of diffusion

controlled drug release reservoir system.

b) Matrix type: The more common type of

dissolution controlled dosage form as shown in

figure .3. It can be either a drug impregnated sphere

or a drug impregnated tablet, which will be

subjected to slow erosion.

Figure 3: Schematic representation of diffusion

controlled drug release matrix system.

C. Bioerodable and Combination of Diffusion

and Dissolution Systems:

It is characterized by a homogeneous

dispersion of drug in an erodible matrix. (Shown in

figure.4)

Figure 4: Drug delivery from (a) bulk-eroding

and (b) surface-eroding Bio erodible systems.

D. Methods using Ion Exchange: It is based on

the drug resin complex formation when an ionic

solution is kept in contact with ionic resins. The

drug from these complexes gets exchanged in

gastrointestinal tract and released with excess of

Na+ and Cl- present in gastrointestinal tract.

E. Methods using osmotic pressure: It is

characterized by drug surrounded by semi

permeable membrane and release governed by

osmotic pressure.

F. pH Independent formulations: A buffered

controlled release formulation as shown in figure 5,

is prepared by mixing a basic or acidic drug with

one or more buffering agents, granulating with

appropriate pharmaceutical excipients and coating

with GI fluid permeable film forming polymer.

When GI fluid permeates through the membrane

the buffering agent adjusts the fluid inside to

suitable constant pH thereby rendering a constant

rate of drug release.


22

Figure 5: Drug delivery from environmentally

pH sensitive release systems.

G. Altered density formulations: Several

approaches have been developed to prolong the

residence time of drug delivery system in the

gastrointestinal tract.

High-density approach

Low-density approach

Matrix Tablet: (Patel H. Nov Dec 2011)

Advantages of matrix tablet:

Easy to manufacture

Versatile, effective and low cost

Can be made to release high molecular

weight compounds

The sustained release formulations may

maintain therapeutic concentrations over

prolonged periods.

The use of sustain release formulations

avoids the high blood concentration.

Sustain release formulations have the

potential to improve the patient

compliance.

Reduce the toxicity by slowing drug

absorption.

Increase the stability by protecting the

drug from hydrolysis or other derivative

changes in gastrointestinal tract.

Minimize the local and systemic side

effects.

Improvement in treatment efficacy.

Minimize drug accumulation with chronic

dosing.

Usage of less total drug.

Improvement the bioavailability of some

drugs.

Improvement of the ability to provide

special effects. Ex: Morning relief of

arthritis through bed time dosing.

Disadvantages of matrix tablet: (Patel H. Nov

Dec 2011)

The remaining matrix must be removed after the

drug has been released.

High cost of preparation.

The release rates are affected by various factors

such as, food and the rate transit through the gut.

The drug release rates vary with the square root of

time. Release rate continuously diminishes due to

an increase in diffusional resistance and/or a

decrease in effective area at the diffusion front.

However, a substantial sustained effect can be

produced through the use of very slow release

rates, which in many applications are

indistinguishable from zero-order.

Classification Of Matrix Tablets:

On the Basis of Retardant Material Used: Matrix

tablets can be divided in to 5 types.

1. Hydrophobic Matrices (Plastic matrices):

The concept of using hydrophobic or inert

materials as matrix materials was first introduced in

1959. In this method of obtaining sustained release

from an oral dosage form, drug is mixed with an

inert or hydrophobic polymer and then compressed

in to a tablet. Sustained release is produced due to

the fact that the dissolving drug has diffused

through a network of channels that exist between

compacted polymer particles. Examples of

materials that have been used as inert or

hydrophobic matrices include polyethylene,

polyvinyl chloride, ethyl cellulose and acrylate

polymers and their copolymers. The rate-

controlling step in these formulations is liquid

penetration into the matrix. The possible

mechanism of release of drug in such type of

tablets is diffusion. Such types of matrix tablets

become inert in the presence of water and

gastrointestinal fluid.

2. Lipid Matrices:

These matrices prepared by the lipid waxes and

related materials. Drug release from such matrices

occurs through both pore diffusion and erosion.

Release characteristics are therefore more sensitive

to digestive fluid composition than to totally

insoluble polymer matrix. Carnauba wax in

combination with stearyl alcohol or stearic acid has

been utilized for retardant base for many sustained

release formulation.


23

3. Hydrophilic Matrices:

Hydrophilic polymer matrix systems are widely

used in oral controlled drug delivery because of

their flexibility to obtain a desirable drug release

profile, cost effectiveness, and broad regulatory

acceptance. The formulation of the drugs in

gelatinous capsules or more frequently, in tablets,

using hydrophilic polymers with high gelling

capacities as base excipients is of particular interest

in the field of controlled release. Infect a matrix is

defined as well mixed composite of one or more

drugs with a gelling agent (hydrophilic polymer).

These systems are called swellable controlled

release systems. The polymers used in the

preparation of hydrophilic matrices are divided in

to three broad groups,

A. Cellulose derivatives: Methylcellulose 400 and

4000cPs, HEC; HPMC 25, 100, 4000 and

15000cPs; and Sodium carboxymethylcellulose.

B. Non cellulose natural or semi synthetic

polymers: Agar-Agar; Carob gum; Alginates;

Molasses; Polysaccharides of mannose and

galactose, Chitosan and Modified starches.

4. Biodegradable Matrices: These consist of the

polymers which comprised of monomers linked to

one another through functional groups and have

unstable linkage in the backbone. They are

biologically degraded or eroded by enzymes

generated by surrounding living cells or by

nonenzymetic process in to oligomers and

monomers that can be metabolized or excreted.

Examples are natural polymers such as proteins and

polysaccharides; modified natural polymers;

synthetic polymers such as aliphatic poly (esters)

and poly anhydrides.

5. Mineral Matrices: These consist of polymers

which are obtained from various species of

seaweeds. Example is Alginic acid which is a

hydrophilic carbohydrate obtained from species of

brown seaweeds (Phaephyceae) by the use of dilute

alkali.

On the Basis of Porosity of Matrix: Matrix

system can also be classified according to their

porosity and consequently, Macro porous; Micro

porous and Non-porous systems can be identified:

1. Macro porous Systems: In such systems the

diffusion of drug occurs through pores of matrix,

which are of size range 0.1 to 1 m. This pore size

is larger than diffusant molecule size.

2. Micro porous System: Diffusion in this type of

system occurs essentially through pores. For micro

porous systems, pore size ranges between 50 200

A, which is slightly larger than diffusant

molecules size.

3. Non-porous System: Non-porous systems have

no pores and the molecules diffuse through the

network meshes. In this case, only the polymeric

phase exists and no pore phase is present.

Polymers used in matrix tablet:

Hydrogels: Polyhydroxyethylemethylacrylate

(PHEMA), Cross-linked polyvinyl alcohol (PVA),

Cross-linked polyvinyl pyrrolidone (PVP),

Polyethylene oxide (PEO), Polyacrylamide (PA)

Soluble polymers: Polyethyleneglycol (PEG),

polyvinyl alcohol (PVA), Polyvinylpyrrolidone

(PVP), Hydroxypropyl methyl cellulose (HPMC)

Biodegradable polymers: Polylactic acid (PLA),

Polyglycolic acid (PGA), Polycaprolactone (PCL),

Polyanhydrides, Polyorthoesters

Non-biodegradable polymers: Polyethylene vinyl

acetate (PVA), Polydimethylsiloxane (PDS),

Polyether urethane (PEU), Polyvinyl chloride

(PVC), Cellulose acetate (CA), Ethyl cellulose

(EC)

Mucoadhesive polymers: Polycarbophil, Sodium

carboxymethyl cellulose, Polyacrylic acid,

Tragacanth, Methyl cellulose, Pectin

Natural gums: Xanthan gum, Guar gum, Karaya

gum, Locust bean gum

Components of matrix tablets: (ME. 2005)

These include:

Active drug

Release controlling agent(s): matrix

formers

Matrix Modifiers, such as channelling

agents and wicking agents

Solubilizers and pH modifiers

Lubricants and flow aid

Supplementary coatings to extend lag time

further reduce drug release etc.

Density modifiers (if required)


24

Mechanism Of Drug Release From Matrix

Tablet:

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 the solid

drug moving toward the interior. It follows that 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. Derivation of the

mathematical model to describe this system

involves the following assumptions:

a) A pseudo-steady state is maintained during drug

release,

b) The diameter of the drug particles is less than

the average distance of drug diffusion through the

matrix,

c) The bathing solution provides sink conditions at

all times.

The release behaviour for the system can be

mathematically described by the following

equation:

dM/dh = Co. dh - 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

matrix

Cs = Saturated concentration of the drug within the

matrix.

Additionally, according to diffusion theory:

dM = ( Dm. Cs / h) dt........................... (2)

Where, Dm = Diffusion coefficient in the matrix.

h = Thickness of the drug-depleted matrix

dt = Change in time

By combining equation 1 and equation 2 and

integrating:

M = [Cs. Dm (2Co Cs) t] (3)

When the amount of drug is in excess of the

saturation concentration then:

M = [2Cs.Dm.Co.t] 1/2 (4)

Equation 3 and equation 4 relate the amount of

drug release to the square-root of time. Therefore,

if a system is predominantly diffusion controlled,

then it is expected that a plot of the drug release vs.

square root of time will result in a straight line.

Drug release from a porous monolithic matrix

involves the simultaneous penetration of

surrounding liquid, dissolution of drug and

leaching out of the drug through tortuous interstitial

channels and pores.

The volume and length of the openings must be

accounted for in the drug release from a porous or

granular matrix:

M = [Ds. Ca. p/T. (2Co p.Ca) t] 1/2

. (5)

Where, p = Porosity of the matrix

t = Tortuosity Ca = solubility of the drug in the

release medium

Ds = Diffusion coefficient in the release medium.

T = Diffusional path length For pseudo steady

state,

the equation can be written as:

M = [2D.Ca .Co (p/T) t]

.. (6)

The total porosity of the matrix can be calculated

with the following equation:

p = pa + Ca/ + Cex / ex

(7)

Where, p = Porosity

= Drug density

pa = Porosity due to air pockets in the matrix

ex = Density of the water soluble excipients

Cex = Concentration of water soluble excipients

For the purpose of data treatment, equation 7 can

be reduced to: M = k. t 1/2 ..

(8)

Where, k is a constant, so that the amount of drug

released versus the square root of time will be

linear, if the release of drug from matrix is

diffusion-controlled. If this is the case, the release

of drug from a homogeneous matrix system can be

controlled by varying the following parameters:

Initial concentration of drug in the matrix

Porosity

Tortuosity

Polymer system forming the matrix

Solubility of the drug.

Effect Of Release Limiting Factor On Drug

Release:

The mechanistic analysis of controlled release of

drug reveals that partition coefficient; diffusivity;

diffusional path thickness and other system

parameters play various rate determining roles in

the controlled release of drugs from either capsules,

matrix or sandwich type drug delivery systems.

A. Polymer hydration: It is important to study

polymer hydration/swelling process for the

maximum number of polymers and polymeric

combinations. The more important step in

polymer dissolution include

absorption/adsorption of water in more


25

accessible places, rupture of polymer-polymer

linking with the simultaneous forming of

water-polymer linking, separation of

polymeric chains, swelling and finally

dispersion of polymeric chain in dissolution

medium

B. Drug solubility: Molecular size and water

solubility of drug are important determinants

in the release of drug from swelling and

erosion controlled polymeric matrices. For

drugs with reasonable aqueous solubility,

release of drugs occurs by dissolution in

infiltrating medium and for drugs with poor

solubility release occurs by both dissolution of

drug and dissolution of drug particles through

erosion of the matrix tablet.

C. Solution solubility: In view of in vivo

(biological) sink condition maintained actively by

hem perfusion, it is logical that all the in vitro drug

release studies should also be conducted under

perfect sink condition. In this way a better

simulation and correlation of in vitro drug release

profile with in vivo drug administration can be

achieved. It is necessary to maintain a sink

condition so that the release of drug is controlled

solely by the delivery system and is not affected or

complicated by solubility factor.

D. Polymer diffusivity: The diffusion of small

molecules in polymer structure is energy activated

process in which the diffusant molecules moves to

a successive series of equilibrium position when a

sufficient amount of energy of activation for

diffusion Ed has been acquired by the diffusant is

dependent on length of polymer chain segment,

cross linking and crystallinity of polymer. The

release of drug may be attributed to the three

factors viz,

i. Polymer particle size

ii. Polymer viscosity

iii. Polymer concentration.

i. Polymer particle size: Malamataris

stated that when the content of hydroxyl

propyl methylcellulose is higher, the

effect of particle size is less important on

the release rate of propranolol

hydrochloride, the effect of this variable

more important when the content of

polymer is low. He also justified these

results by considering that in certain areas

of matrix containing low levels of

hydroxyl propyl methylcellulose led to

the burst release.

ii. Polymer viscosity: With cellulose ether

polymers, viscosity is used as an

indication of matrix weight. Increasing

the molecular weight or viscosity of the

polymer in the matrix formulation

increases the gel layer viscosity and thus

slows drug dissolution. Also, the greater

viscosity of the gel, the more resistant the

gel is to dilution and erosion, thus

controlling the drug dissolution.

iii. Polymer concentration: An increase in

polymer concentration causes an increase

in the viscosity of gel as well as

formulation of gel layer with a longer

diffusional path. This could cause a

decrease in the effective diffusion

coefficient of the drug and therefore

reduction in drug release. The mechanism

of drug release from matrix also changes

from erosion to diffusion as the polymer

concentration increases.

E. Thickness of polymer diffusional path: The

controlled release of a drug from both capsule and

matrix type polymeric drug delivery system is

essentially governed by Ficks law of diffusion:

JD = D dc/dx

Where, JD is flux of diffusion across a plane

surface of unit area

D is diffusibility of drug molecule, dc/dx is

concentration gradient of drug molecule across a

diffusion path with thickness dx.

F. Thickness of hydrodynamic diffusion layer: It

was observed that the drug release profile is a

function of the variation in thickness of

hydrodynamic diffusion layer on the surface of

matrix type delivery devices. The magnitude of

drug release value decreases on increasing the

thickness of hydrodynamic diffusion layer d.

G. Drug loading dose: The loading dose of drug

has a significant effect on resulting release kinetics

along with drug solubility. The effect of initial drug

loading of the tablets on the resulting release

kinetics is more complex in case of poorly water

soluble drugs, with increasing initial drug loading

the relative release rate first decreases and then

increases, whereas, absolute release rate

monotonically increases. In case of freely water

soluble drugs, the porosity of matrix upon drug

depletion increases with increasing initial drug


26

loading. This effect leads to increased absolute

drug transfer rate. But in case of poorly water

soluble drugs another phenomenon also has to be

taken in to account. When the amount of drug

present at certain position within the matrix,

exceeds the amount of drug soluble under given

conditions, the excess of drug has to be considered

as non-dissolved and thus not available for

diffusion. The solid drug remains within tablet, on

increasing the initial drug loading of poorly water

soluble drugs, the excess of drug remaining with in

matrix increases.

H. Surface area and volume: The dependence of

the rate of drug release on the surface area of drug

delivery device is well known theoretically and

experimentally. Both the in vitro and in vivo rate of

the drug release, are observed to be dependent upon

surface area of dosage form. Siepman et al. found

that release from small tablet is faster than large

cylindrical tablets.

I. Diluents effect: The effect of diluent or filler

depends upon the nature of diluent. Water soluble

diluents like lactose cause marked increase in drug

release rate and release mechanism is also shifted

towards Fickian diffusion; while insoluble diluents

like dicalcium phosphate reduce the Fickian

diffusion and increase the relaxation (erosion) rate

of matrix. The reason behind this is that water

soluble filler in matrices stimulate the water

penetration in to inner part of matrix, due to

increase in hydrophilicity of the system, causing

rapid diffusion of drug, leads to increased drug

release rate.

J. Additives: The effect of adding non-polymeric

excipients to a polymeric matrix has been claimed

to produce increase in release rate of hydro soluble

active principles. These increases in release rate

would be marked if the excipients are soluble like

lactose and less important if the excipients are

insoluble like tricalcium phosphate

.

Biological Factors Influencing Release from

Matrix Tablet:

Biological half-life.

Absorption.

Metabolism

Distribution

Protein binding

Margin of safety

Biological half-life: The usual goal of an oral SR

product is to maintain therapeutic blood levels over

an extended period of time. To achieve this, drug

must enter the circulation at approximately the

same rate at which it is eliminated. The elimination

rate is quantitatively described by the half-life

(t1/2). Each drug has its own characteristic

elimination rate, which is the sum of all elimination

processes, including metabolism, urinary excretion

and all over processes that permanently remove

drug from the blood stream. Therapeutic

compounds with short half-life are generally are

excellent candidate for SR formulation, as this can

reduce dosing frequency. In general, drugs with

half-life shorter than 2 hours such as furosemide or

levodopa are poor candidates for SR preparation.

Compounds with long half-lives, more than 8 hours

are also generally not used in sustaining form, since

their effect is already sustained. Digoxin and

phenytoin are the examples.

Absorption: Since the purpose of forming a SR

product is to place control on the delivery system, it

is necessary that the rate of release is much slower

than the rate of absorption. If we assume that the

transit time of most drugs in the absorptive areas of

the GI tract is about 8-12 hours, the maximum half-

life for absorption should be approximately 3-4

hours; otherwise, the device will pass out of the

potential absorptive regions before drug release is

complete. Thus corresponds to a minimum

apparent absorption rate constant of 0.17-0.23h-1 to

give 80-95% over this time period. Hence, it

assumes that the absorption of the drug should

occur at a relatively uniform rate over the entire

length of small intestine. For many compounds this

is not true. If a drug is absorbed by active transport

or transport is limited to a specific region of

intestine, SR preparation may be disadvantageous

to absorption. One method to provide sustaining

mechanisms of delivery for compounds tries to

maintain them within the stomach. This allows

slow release of the drug, which then travels to the

absorptive site. These methods have been

developed as a consequence of the observation that

co-administration results in sustaining effect. One

such attempt is to formulate low density pellet or

capsule. Another approach is that of bio adhesive

materials.

Metabolism: Drugs those are significantly

metabolized before absorption, either in the lumen

or the tissue of the intestine, can show decreased

bioavailability from slower-releasing dosage form.


27

Hence criteria for the drug to be used for

formulating Sustained-Release dosage form is,

Drug should have law half-life (


28

DRUGS USED CATEGORY METHOD USED POLYMER USED

Zidovudine Anti-viral Direct Compression HPMC-K4M, Carbopol-934, EC

Venlafexine Anti-depressant Wet Granulation Beeswax, Carnauba wax

Domperidone Anti-emetic Wet Granulation HPMC-K4M, Carbopol-934

Alfuzosin Alfa-adrenergic

Agonist

Direct Compression HPMC-K15M, Eudragit-RSPO

Minocycline Antibiotic Wet Granulation HPMC-K4M, HPMC-K15M, EC

Ibuprofen Anti-

inflammatory

Wet Granulation EC, CAP

Metformin HCL Anti-diabetic Direct Compression HPMC-K100M, EC

Propranolol HCL Beta-adrenergic

blocker

Wet Granulation Locust bean gum, HPMC

Furosemide Anti-diuretic Direct Compression Guar gum, Pectin, Xanthan gum

Acarbose Anti-diabetic Direct Compression HPMC, Eudragit

Aceclofenac Anti-

inflammatory

Wet Granulation HPMC-K4M,K15M,

K100M,E15,EC, Guar gum

Ambroxol HCL Expectorent,

Mucolytic

Direct Compression HPMC-K100M,

Aspirin Anti-

inflammatory

Direct Compression EC, Eudragit-RS100, S100

Diclofenac Na Anti-

inflammatory

Wet Granulation Chitoson, EC, HPMCP, HPMC

Diethylcarbamazepine

citrate

Anti-filarial Wet Granulation Guar gum, HPMC-E15LV

Diltiazem Ca+2 channel

blocker

Direct Compression HPMC-K100M, HPMC-K4M,

Karaya gum, Locust bean gum,

Sod.CMC

Enalpril meleate ACE inhibitor Direct Compression HPMC-K100M,HPMC K4M,

Flutamide Anti-androgen Direct Compression HPMC-K4M, Sod.CMC, Guar gum,

Xanthan gum

Indomethacin Anti-

inflammatory

Direct Compression EC, HPMC

Chlorphenarimine

meleate

H1 antagonist Melt-extrusion Xanthan gum,Chitoson

Itopride HCL Prokinetic agent Direct Compression HPMC-K100M, HPMC-K4M, EC

Losartan potassium Anti-hypertensive Direct Compression HPMC-K100M, HPMC-K4M,

Eudragit-RSPO

Metoclopromide Anti-emetic Direct Compression /

Wet Granulation

HPMC, CMC, EC, SSG

Miconazole Anti-fungal Direct Compression /

Wet Granulation

Pectin, HPMC

Naproxen Morphine

antagonist

Direct Compression HPMC-K100M, HPMC-K15M, PVP

Nicorandil Ca+2 channel

blocker

Wet Granulation HPMC, CMC, EC

Ondansertan Anti-hypertensive Wet Granulation HPMC-K100M, HPMC-K4M,

HPMC-K15M

Phenytoin Na Anti-epileptic Wet Granulation Tragacanth, Acacia, Guar gum,

Xanthan gum

Ranitidine HCL H2 antagonist Direct Compression Chitoson, Carbopol-940

Theophylline Respiratory

depressant

Direct Compression Carbopol-934P, HPMC-K100M,

HPMC-K4M, HPMC-K15M, EC


29

Osmotic Drug Delivery:

Introduction (M. 2009)

Controlled release dosage form are designed to

release drug in-vivo according to predictable rate that

can be verified by in-vitro measurement Potential

development and new approaches to oral controlled

release dosage form includes,

1. Hydrodynamic pressure controlled system

2. Intragastric floating tablet

3. Transmucosal tablet

4. Microporous membrane coated tablet.

Advantages: (Ghosh T. 2011)

Decrease frequency of dosing.

Reduce the rate of rise of drug concentration

in the body.

Delivery may be pulsed or desired if

required.

Delivery ratio is independent of pH of the

environment.

Delivery is independent of hydrodynamic

condition, this suggest that drug delivery is

independent of G.I. motility.

Sustained and consistence blood level of

drug within the therapeutic window.

Improve patient compliance.

High degree of in vitro- in vivo correlation

is obtained in osmotic system.

Reduce side effect.

Delivery rate is also independent of delivery

orifice size within the limit.

Disadvantage & limitation (Ghosh T. 2011)

OCODDS have produced significant clinical benefit

invarious therapeutic areas .Some system have

enhanced patient compliance, while other has

minimized the side effect of their active compounds.

However some limitations of OCODDS have been

reported.

Slightly higher cost of good than matrix

tablet or multiparticulates ion capsule

dosage form.

Gastro intestinal obstruction cases have been

observed with the patient receiving

Nifedipine GITS tablet.

Another case was reported for osmosin

(Indomethacin OROS) which was first

introduced in the United Kingdom in 1983

.A few month later after its introduction

frequent incidences of serious

gastrointestinal reaction was observed

leading to osmosin withdrawal. Various

explanations were given based on the toxic

effect of KCl used in osmosin.

Magnetic resonance imaging (MRI) of tablet

elucidate that nonuniform coating leads to

different pattern of drug release among the

batches.

What Is Osmotic Pressure: (M. 2009)

Osmosis

Osmosis can be defined as the net movement of water

across a selectively permeable membrane driven by a

difference in osmotic pressure across the membrane.

It is driven by a difference in solute concentrations

across the membrane that allows passage of water,

but rejects most solute molecules or ions. Osmotic

pressure is the pressure which, if applied to the more

concentrated solution, would prevent transport of

water across the semipermeable membrane.

The first osmotic effect was reported by Abbe Nollet

in 1748. Later in 1877, Pfeffer performed an

experiment using semi-permeable membrane to

separate sugar solution from pure water. He showed

that the osmotic pressure of the sugar solution is

directly proportional to the solution concentration

and the absolute temperature. In 1886, Vant Hoff

identified an underlying proportiona

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Drug Delivery Systems a Review

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