NDDS Introduction

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 Just as cars are useless without roads, drugs are useless

without an effective delivery system.

 The active ingredient in a medicine is only part of the

arsenal against disease.

 The drug must somehow get to the right place at the

right time. That’s where drug delivery comes in.

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 Drug delivery companies work to devise new dosage forms

for medications to place the drug.

 Historically, this has meant product life-cycle management, a

process in which a pharmaceutical company looks for ways

to set apart a product reaching the end of its patent.

 For example, a company might tinker with a drug that

patients must take multiple times a day and reduce that to a

single dose.

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Nowadays, the competition is so intense in the

pharmaceutical marketplace that companies look to

drug delivery as a way to gain a competitive advantage.

The value that drug delivery adds can be improved

safety, efficacy, convenience, and patient compliance.

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ERA OF DRUG DELIVERY

 As a result of biotechnology development, many people

believe that proteins are going to comprise an increasing

proportion of the new-drug market.

 Many existing peptide and protein drugs are coming off

patent, fueling the interest in developing new dosage

forms.

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 There is the equivalent of a generic industry that will

likely be developed for peptides and proteins,

analogous to [what evolved with] small molecules.

 The race is on to develop alternatives to injection for

macromolecules. The main methods being explored

are pulmonary (inhalation) and oral formulations. In

addition, transdermal and extended-release injectable

formulations are being targeted.

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THIS IS Done for

 Better control of plasma drug levels and less frequent

dosing.

 For Linear one compartment PK drugs:

Dose interval (ּד) < t1/2

TI is therapeutic index = LD50/ED50

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The dosing interval may be increased by :

 Modifying the drug molecule to decrease
the rate of elimination.

OR
 Modifying the release rate of a dosage

form to decrease the rate of absorption.

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Drug delivery system

 Goal of any drug delivery system is to provide a

therapeutic amount of a drug to a proper site in the

body so that the desired concentration can be

achieved promptly and then maintained.

 Drug delivery system should deliver the drug dictated

by the needs of the body over a specified period of

time.

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 This involves two aspects most important for drug delivery.

 Spatial placement – related to targeting drugs to special

tissues, organs or cells.

 Temporal delivery refers to controlling the rate of drug

delivery to target site.

 Science and technology is responsible for development of

these aspects.

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Conventional drug delivery

 Oral

 Parentral route – IV

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Problems inherent in multiple dose therapy –

1. Large peaks and valleys

2. Drug conc. May not be within therapeutic range for
long time.

3. Patient non compliance with multiple therapy.

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An Ideal Drug Delivery System

1. Release rate dictated by the needs of the body over

the period of treatment

 Constant, 0-order

2. Channel the drug to the active site, cell, tissue, organ

(drug targeting)

3. “No such DDS exists which combines 1 and 2…!!!”

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Terminology

 Systems which can provide “some” control of drug

release in the body

 Temporal

 Spatial

 Both

 Specify release rate and duration in vivo by simple in

vitro tests

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 Delayed release systems – are either those that use repetitive,

intermittent dosing of a drug from one or more immediate

release units incorporated into a single dosage form, or an

enteric delayed release system.

e.g. repeat action tablet, enteric coated tablet,

 Extended release system – systems include any dosage form

that maintains therapeutic blood or tissue level of the drug for a

prolonged period.

Extended release is not equivalent to controlled release.

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 Site specific or receptor targeting – refer to targeting a

drug directly to a certain biological location. The target is

adjacent to or in the diseases organ or tissue.

 Controlled drug delivery – can be defined as delivery of a

drug at a pre determined rate and/or to a location

according to the needs of the body and disease states for

a definite period of time.

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Controlled Delivery Attempts to:
1. Extend drug action at a predetermined rate by maintaining a relatively

constant, effective drug level in the body with concomitant minimization

of undesirable side effects associated with a saw – tooth kinetic pattern

of conventional release.

2. Localize drug action by spatial placement of a controlled release system

(usually rate controlled) adjacent to or in the diseased tissue or organ

3. Target drug action by using carriers or chemical derivatization to deliver

drugs to a particular “target” cell type

4. Provide a physiologically/therapeutically based drug release system

means that the amount and rate of drug release are determined by the

physiological/ therapeutic needs of the body.

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Controlled Release vs. Sustained Release

 Sustained release

 Complexation, slowly dissolving coatings, use of derivatives with

reduced solubility

 Sensitive to environmental conditions to which they are exposed

 Sustains drug level for prolonged time.

 Controlled release

 Release rate is determined by the device itself

 More accurate, predictable administration rate

 Controls time as well as site of release.

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Advantages of Controlled drug delivery
systems

1. achieve more effective therapies while eliminating the

potential for both under- and overdosing.

2. the maintenance of drug levels within a desired range.

3. the need for fewer administrations, optimal use of the

drug in question.

4. increased patient compliance.

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 Employ less total drug
A) minimize or eliminate local side effects
B) minimize or eliminate systemic side effects
C) Obtain less potentiation in drug activity with chronic

use.
D) Minimize drug accumulation with chronic dosing
 Improve efficiency in treatment
a) Cure or control condition more promptly
b) Reduce fluctuation in drug level
c) Make use of spatial effects.
E) Economic savings

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Disadvantages of controlled drug delivery

1. The possible toxicity or nonbiocompatibility of the
materials used.

2. Undesirable by-products of degradation.

3. The chance of patient discomfort from the delivery
device for instance if any surgery required to
implant or remove the system.

4. The higher cost of controlled-release systems
compared with traditional pharmaceutical
formulations.

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Controlled drug delivery – history

 1950-1970 – Hydrophobic polymers, waxes used to extend drug

action. Lacks anatomic and physiologic basis.

 1970-1980- Determined needs in CDDS, understanding the barriers

for various routes of administration, zero order importance, drug

targeting.

 1980-1990- Biotechnology research and molecular biology research

 Post1990 – modern era of CDDS, optimization of formulations,

novel polymers, temporal aspect. Newer approaches are allowing

spatial placement as well.

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Factors influencing the design and performance of
a controlled release systems

The design of modified release system is subject to several

variables including route of drug administration, type of

delivery system, disease being treated, patient and length of

therapy.

Most important constraints are imposed by Physico- chemical

properties of drug.

Biological properties of drug are the function of Physico-

chemical properties of drug.

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A) Physico chemical properties

1. Dose size

If an oral product has a dose size greater that 0.5gm it is a

poor candidate for sustained release system

in most cases generates a substantial volume product that

unacceptably large.

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 Aqueous Solubility :

dc/dt = K A Cs

Dc/dt – rate of dissolution

K – dissolution rate constant

A – surface area of dosage form

Cs – aq. solubility of drug

Drugs aqueous solubility will generally be decreased by conversion to an

unchanged form for drugs with low water solubility will be difficult to

incorporate into sustained release mechanism.

Extremes of solubility of drug are unsuitable for formulation.

The lower limit on solubility for such product has been reported 0.1mg/ml.

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 Aqueous Solubility :

since the unchanged form of a drug preferentially permeates

across lipid membranes.

Drugs aqueous solubility will generally be decreased by

conversion to an unchanged form for drugs with low

water solubility will be difficult to incorporate into

sustained release mechanism.

The lower limit on solubility for such product has been

reported 0.1mg/ml.
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 Pka

The relationship between Pka of compound and pH of

absorptive environment.

Presenting drug in an unchanged form is adventitious for

drug permeation but solubility decrease as the drug is in

unchanged form. (pH partition hypothesis)

 St = So (1 + 10pH – pKa )

R = (1 + 10pHb – pKa ) / (1 + 10pHg – pKa )

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 E.g. aspirin

pHb – 7.4

pHg – 2

Pka of aspirin – 3.4

Therefore – R = 3.4 or 4

And pHi – 7

Therefore – R = 1

Hence more absorption is from stomach where it is in
unionized form.

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 Pka

The relationship between Pka of compound and absorptive

environment.

Presenting drug in an unchanged form is adventitious for

drug permeation but solubility decrease as the drug is in

unchanged form

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 Partition Coefficient

Defined as the fraction of drug in an oil phase to that of an

adjacent aqueous phase.

high partition coefficient – predominantly lipid soluble

consequently have very law aqueous solubility.

Low partition coefficients – difficulty in penetrating

membranes resulting poor bioavailability.

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 Drug Stability

Orally administered drugs can be subject to both acid base

hydrolysis and enzymatic degradation.

drugs that are unstable in stomach, systems that prolong

delivery ever the entire course of transit in GI tract are

beneficial.

Compounds that are unstable in the small intestine may

demonstrate decreased bioavailability when administered

from a sustaining dosage from.

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 Drug unstable In stomach are formulated to deliver

contents in intestine and drugs unstable in intestine

should release contents in stomach.

 Delivery systems that are localized in particular area are

proffered . E.g. bio adhesive systems that are localized and

act as reservoir of drug.

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 Drug Stability

Orally administered drugs can be subject to both acid base

hydrolysis and enzymatic degradation.

drugs that are unstable in stomach, systems that prolong

delivery ever the entire course of transit in GI tract are

beneficial.

Compounds that are unstable in the small intestine may

demonstrate decreased bioavailability when administered

from a sustaining dosage from.

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 Molecular size and diffusivity:
The ability to diffuse through membranes – called diffusivity

& diffusion coefficient is function of molecular size (or
molecular weight)

logD= -Sv logV + Kv
logD= -Sm logM+ Km

values of diffusion coefficient – 10-8 to 10-9 cm2 / sec.
10-8 being most common for drugs with molecular weight

up to 500
Large molecular weight drugs display very slow release

kinetics in sustained release device

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 Molecular size and diffusivity:

The ability to diffuse through membranes – called diffusivity
& diffusion coefficient is function of molecular size (or
molecular weight)

values of diffusion coefficient – 10-8 to 10-9 cm2 / sec.

10-8 being most common for drugs with molecular weight
up to 500

Large molecular weight drugs display very slow release
kinetics in sustained release device

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 Protein binding

Many drugs bind to plasma proteins with a concomitant

influence on the duration of drug action.

Drug Protein binding can serve as a depot for drug

producing a prolonged release profile.

Extensive binding to plasma proteins will be evidenced by a

long half life of elimination for drugs.

Eg. amitryptyline. diazepam, diazoxide, dicumarol

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B) Biological factors:
Release rate and dose

The goal of controlled drug delivery is
K0

r = Rate in = Rate out = Ke Cd Vd
W= Di +Dm
Consist of two doses Di that releases drug immediately and a

maintenance dose Dm,
For zero order release
W= Di + K0

r Td
Td time required for extended release from one dose.
W= Di + K0

r Td – K0
r Tp

K0
r Tp is amount of drug provided during the period t =0 to the time
of peak drug level, Tp.

No correction is needed if system does not begin to release drug
until time Tp.

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For first order process
W= Di + Ke Cd/ KrVd
Kr first order release rate
If maintenance dose begin to release drug at t= 0 a correction

factor is needed
W= Di + Ke Cd/ KrVd – Dm Ke Tp
Extended release system is designed to alleviate repetitive

dosing, it naturally will contain greater amount of drug than
corresponding conventional dosage form.

For IM, SC, IV route the tolerance may be produced at site of
injection due to large size.

For potent drugs, incorporation of large amount of drugs is
potentially dangerous if system fails to control release.

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B) Biological factors:

Elimination and Biological Half Life

The rate of elimination of a drug is described quantitatively
by its biological half life. And given by

T1/2 = 0.693V/Cl = 0.693 V. AUC/dose (since Cl =dose/AUC)

Under steady state

Ri = R0

R0 = Css Cl

Half life helpful to Determine dosing interval.

Therapeutic compounds with short half lives are excellent
candidates for sustained release preparations. Since this
can reduce dosing frequency.

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In general drugs with half-lives shorter than 2hrs are poor

candidates of sustained release dosage forms as dose size

and large release rates are required. Eg. Ampicilin,

levodopa, penicilin.

As well as compounds with long half lives, more than 8 hrs

are also not used in sustained release forms because their

effect is already sustained. E.g. diazepam, digoxin,

phenytoin.

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Absorption:
As the rate limiting step in drug delivery from a sustained-release

system is its release from a dosage form, rather than absorption.
(Kr <<<< Ka)

Rapid rate of absorption of drug, relative to its release is essential if
the system is to be successful.

It we assume that transit time of drug must in the absorptive areas
of the GI tract is about 9-12 hrs.

The maximum half life for absorption should be approximately 3-4
hrs.

Absorption rate constant should be between 0.17 to 0.23 hr-1 for
80- 95% absorption in transit of 9-12hrs.

Therefore release rate should be less than 0.17 hr-1

Slowly absorbed drugs will be difficult to formulate into extended
release systems where this criteria of Kr <<<< Ka must be met.

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 Extent of absorption is low that means Bioavailability of

drug is low for variety of reasons like poor water

solubility, low partition coefficient, acid hydrolysis,

metabolism, site specific absorption.

 These problems can be overcome by appropriately

designed extended release system.

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Absorption:
As the rate limiting step in drug delivery from a sustained-

release system is its release from a dosage form, rather than
absorption. (Kr <<<< Ka)

Rapid rate of absorption of drug, relative to its release is
essential if the system is to be successful.

It we assume that transit time of drug must in the absorptive
areas of the GI tract is about 8-12 hrs.

The maximum half life for absorption should be approximately
3-4 hrs.

Absorption rate constant should be between 0.17 to 0.23 hr-1

Therefore release rate should be less than 0.17 hr-1 which is
practically difficult. It result in unacceptable lower
bioavailability.

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 Distribution

The distribution is important factor in the overall drug

elimination kinetics.

Since it not only lowers the concentration of circulating drug but

it also can be rate limiting in its equilibrium with blood and

extra vascular tissue.

It restricts magnitude of release rate and dose size.

For design of sustained/ controlled release products, one must

have information of disposition of drug.

Two important factor are – Volume of distribution and T/P ratio

is needed.
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 V=dose/Co

 Greater is V needs for larger dose and frequent
administration

 T/P= K12 (K21 – β)

β disposition rate constant.

T/P determines relative distribution of drug between
compartments

Vss determines extent of distribution in body.

Both contributes for estimation of distribution
characteristics.

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 Metabolism
 The location, rate and extent of metabolism should be known

to formulate successful extended release system.

Drugs that are significantly metabolized before absorption, either

in lumen or the tissue of the intestine, can show decreased

bioavailability.

Intestinal metabolism – salicylamide, nitroglycerine, levodopa,

isoproterenol, chlorpromazine.

As drug is released at a slower rate to these regions less total

drug is presented to the enzymatic degradation.

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 Fluctuation in drug blood level due to first pass effect.

 First pass effect – phenacetin, propranolol, lidocaine.

 These are suitable candidates for modified release system

 Enzyme inhibitors – cimetidine, ciprofloxacin, fluconazole

increases conc. Of drg due to enzyme inhobition.

 Enzyme inducers – Carbamazepine, phenobarbital, rifampin

are inducers therefore increased metabolism reduces conc.

Of drug.

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 A drug can be both metabolized by and inhibit the same enzyme (e.g.,

erythromycin), or it can be metabolized by one enzyme and inhibit

another enzyme (e.g., terbinafine).

 Drugs may be intentionally combined to take advantage of CYP450

inhibition. Ritonavir a protease inhibitor and potent CYP3A4 inhibitor, is

added to lopinavir to boost serum levels in patients with human

immunodeficiency virus.

 These factors of first pass metabolism, drug degradation in GI tract,

enzyme inhibition and induction are to consider for modified release

systems.

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 Metabolism

Drugs that are significantly metabolized before absorption,

either in lumen or the tissue of the intestine, can show

decreased bioavailability.

Intestinal metabolism – salicylamide, nitroglycerine,

levodopa

As drug is released at a slower rate to these regions less

total drug is presented to the enzymatic degradation.

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 Flactuation in drug blood level due to first pass effect.

 First pass effect – phenacetin, propranolol, lidocaine.

 These are suitable candidates for modified release system

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 Protein binding

Many drugs bind to plasma proteins with a concomitant

influence on the duration of drug action.

Drug Protein binding can serve as a depot for drug

producing a prolonged release profile.

Extensive binding to plasma proteins will be evidenced by a

long half life of elimination for drugs.

Eg. amitryptyline, diazepam, diazoxide

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Elimination and Biological Half Life

The rate of elimination of a drug is described quantitatively
by its biological half life. And given by

T1/2 = 0.693V/Cl = 0.693 V. AUC/dose

(since Cl =dose/AUC)

For achieving control release we need

Ri = R0

R0 = Css Cl

Input rate is determined by steady state conc. And systemic
clearance.

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Half life helpful to Determine dosing interval.

Therapeutic compounds with short half lives are excellent

candidates for sustained release preparations. Since this

can reduce dosing frequency.

Drugs with long half life is dosed at greater time intervals,

thus there is less need for extended release systems.

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In general drugs with half-lives shorter than 2hrs are poor

candidates of sustained release dosage forms as dose size

and large release rates are required. Eg. Ampicilin,

levodopa, penicilin, furosemide,

As well as compounds with long half lives, more than 8 hrs

are also not used in sustained release forms because their

effect is already sustained. E.g. diazepam, digoxin,

phenytoin, warfarin.

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Efficacy and safety

 Have a thorough knowledge of relationship between

concentration and effect and its dependence on disease and time

profile of drug input to have a more rational design of extended

release delivery system.

 PK/PD model is required to obtain a rational design of extended
release dosage form.

 E.g. a constant drug blood level does not necessarily produce a
constant pharmacological effect in some cases

Nitroglycerin – a constant level leads to tolerance and result in
decreased pharmacological effect. Hence an OFF period is
required for adequate nitroglycerin therapy.

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Therapeutic index

Above therapeutic conc., result in increasing toxic effects
and a fall off in desired therapeutic response observed
below this range.

TI = TD50/ED50

TD50 median toxic dose

ED50 median effective dose.

For potent drugs therapeutic conc. Range is narrow and
value of TI is small.

Larger the value of TI the safer is drug.

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 Drugs with very small values of TI are poor candidates

for formulations into extended release products.

 TI value should be above 10. Below 10 are barbiturates

and cardiac glycosides.

 Controlled release system can minimize side effects for a

particular drug by controlling its plasma conc. And using

less total drug over the time course of therapy.

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Other factors

 Release rate and dose

 Efficacy and safety,

 therapeutic index

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Compounds Those Are Unsuitable For
Controlled Release

 Drugs with elimination half life less than two hrs

 Drugs those that are administered in large doses

 Administering drugs like warfarin, whose pharmacological effect

is delayed relative to its blood profile, offers no clinical advantage.

 Incorporating drugs like fluorouracil, and perhaps some beta

lactum antibiotics and thiamine diuretics that appears to exhibit

an “absorption window” may reduce absorption efficiency.

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References

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