Introduction, Definitions, Advantages and Disadvantages, Selection of drug candidates for designing controlled drug release systems and rationale biological and medical rationale
2. INTRODUCTION
What is Drug Delivery System?
Drug delivery refers to approaches used to deliver drugs at the target sites inside
our body
An Ideal drug delivery system should be
Inert
Biocompatible
Mechanically strong
Comfortable for the patient
Capable of achieving high drug loading
Safe from accidental release
Simple to administer and remove
Easy to fabricate and sterilize
3. Overview of the drug delivery system development from basic research to clinical applications. The main components
of drug delivery systems and processes are shown in bold face and a solid box, and subsections of each component
are shown in a dotted box
4. Limitations of Conventional Drug Delivery Systems
• Poor patient compliance as the complete dosage regimen needs more than twice or thrice
a day administration, which multiplies the chances of missing a dose, especially in the
case of geriatric and pediatric patients
• Due to the frequent dosing with fluctuating drug concentration-time intervals between the
doses, the plasma drug concentration profile encompasses a combination of alternate
peaks and valleys, which posses a prominent hindrance for the attainment of the desired
steady-state profile
• Due to the immeasurable fluctuations in plasma drug concentration profile, there may be
chances of under or overmedication, that is, at certain points during the therapy the
plasma drug concentration may fall below the minimum effective concentration or may rise
above the maximum safe concentration
5. What is Novel Drug delivery System?
Novel Drug delivery System (NDDS) refers to the approaches, formulations,
technologies and systems for transporting a pharmaceutical compound in the body as
needed to safely achieve its desired therapeutic effects
Simply, NDDS is a system for delivery of drug other than conventional drug
delivery system
NDDS is a combination of advance technique and new dosage forms which are far
better than conventional dosage forms
Advantages of Novel Drug Delivery System are:
Optimum dose at the right time and right location
Efficient use of expensive drugs
Excipients and reduction in production cost
Beneficial to patients with better therapy and improved comfort
Basic modes of Novel drug delivery systems are:
Targeted Drug Delivery System
Controlled Drug Delivery System
Modulated Drug Delivery System
6. The conventional dosage forms, for example, tablets and capsules, provide only a
single and transient bursting of the drug
The problem arises when the results obtained from drugs are above the limit of the
range. So, one of the main reasons for development of CRDDS is to reduce side
effects and improve the safety of drug usage
CRDDS employs drug-encapsulating devices from which therapeutic agents may
be released at controlled rates for long periods of time, ranging from days to
months
Mechanism of CRDDS
Controlled Drug Delivery System
7. What is the difference between SRDDS
and CRDDS?
Sustained release dosage forms follow
first order kinetics whereas Controlled
forms follow zero order kinetics
In sustained forms the dosage is
sustained for prolonged period of time
and drug release is not definite per unit
time but in controlled forms, drug
release is very definite per unit time
Synonyms
CRDDS: Programmed release, Timed release, Repository dosage forms
SRDDS: Prolonged release, Extended release, Depot formulations
10. Drug levels in the blood with-
Traditional drug dosing
The level rises after each
administration of the drug and then
decreases until the next
administration
Controlled delivery dosing
20. Controlled Drug Delivery System
ADVANTAGES
Tailoring of drug release rates
Protection of fragile drugs
Increased patient comfort and compliance
Enhanced efficiency
Favorable reach in plasma levels
Breached side effects and Adverse reactions
System imparts long-term action
Greater drug potential
Interprets the movement of drugs across
biological membranes and ensures a better
understanding of drug transport methods
Carriers delivering drugs to specific target sites
More uniformity in effect
Reduction in total drug usage when compared
with conventional therapy
Reduction in drug accumulation with chronic
therapy
Stabilization of medical condition (because of
more uniform drug levels)
DISADVANTAGES
Possible toxicity or non-biocompatibility of the
materials used
Undesirable by-products of degradation
Surgery required to implant or remove the
system
Chance of patient discomfort from the delivery
device
Delay in onset of drug action
Possibility of dose dumping in the case of a
poor formulation strategy
Increased potential for first pass metabolism
Greater dependence on GI residence time of
dosage form
Possibility of less accurate dose adjustment in
some cases
Cost per unit dose is higher when compared
with conventional doses
Not all drugs are suitable for formulating into
CR dosage form
24. Properties of a drug that make it unsuitable for designing CRDDS
Selection of drug candidates for CRDDS
Some properties of drug candidates make it a poor choice for consideration in
designing of the controlled release system
26. Rationale for Designing Controlled Drug Delivery Systems
Rationale: An underlying reason – the basis
It is a necessary justification for any scientific study
2 types
1. Medical Rationale
2. Biological Rationale
Medical Rationale
Reduction in Dosing Frequency
Lesser Drug Exposure to the
Biological Environment
Minimal blood plasma
concentration fluctuation
Better Patient Compliance
Lower Adverse/Side Effects
Augmented Efficacy
Biological Rationale
Absorption
Drug protein binding
Distribution
Elimination
Dose dependent bioavailability
Duration of drug residence
Better safety margin
Individualization in a diseased
condition
27. 1. Reduction in Dosing Frequency
The conventional therapy usage shows a limitation of frequent dosing, that is, a chance of
skipping a dose; this problem can be reduced if the dosage forms are developed into
CRDDS form thereby releasing the drug for a long time and maintaining the drug
concentration in blood
When the time period between the doses is increased, the number of doses is reduced
from 34 times to 12 times. The novel systems like proteins and peptides can be delivered
into the body using a controlled delivery approach. Tumor therapies also can be improved
by enhanced targeting
Medical Rationale
28. 2. Lesser Drug Exposure to the Biological Environment
The basic rationale behind the CRDDS is the alteration of active metabolites
either pharmacokinetically or pharmacodynamically by using new drug delivery
approaches or by modifying the molecular structure and or physiological
parameters
The controlled release of a drug can be achieved by either temporal control or by
distribution control
a. Temporal control: Enables the system to deliver the drug over an extended
time for a specific period within the treatment regimen. This control proves to be
beneficial for the drugs with a fast metabolism
b. Distribution control: Involved in the targeted delivery of the drug in the body
(i.e.; to control the concentration of drug on the cells and tissues of target sites)
various drugs like steroids, antibiotics, and hormones benefit from both of these
approaches of CRDDS
29. 3. Minimal blood plasma concentration fluctuation
Minimization of Plasma Concentration Fluctuations With the use of conventional tablets or
capsules there occurs only a single and transient type of burst, when the effect of the drug is
above minimum effective concentration. The response is observed pharmacologically, but
when the response is narrow a problem arises; in this case CRDDS reduce fluctuation in
plasma levels by retarding the rate of absorption, which is accompanied by slower drug
release
The modification of drug formulation should be achieved in such a way that fluctuations during
the dosing interval are reduced. This approach is required for the drugs having short half-lives
and low therapeutic index, for which maintenance of therapeutic drug concentrations are
mandatory. This approach results in better patient compliance and reduced chances of toxicity
Ex: Procainamide and Quinidine
30. The development of any dosage form deals with the aim of providing better patient
compatibility The designing of a drug dosage regimen influences the duration of
action of the drug. Factors like bioavailability, absorption rate, and elimination rate
content affect the therapeutic response of a dosage form
The CRDDS are the ideal drug delivery system to deliver the drug at the needed
part of the body over a period a time and have a clear relationship between the
plasma concentration levels and the therapeutic response thereby improved patient
compliance
To improve the bioavailability and therapeutic response of drugs in the body the
drugs that are unstable through the oral route are administered through a different
route, for example, nitroglycerine
The CRDDS is more sophisticated than merely delaying the release, it delivers the
drug with controlled release rates within the specific time period. This system
maintains the drug levels within the required range, requiring few
administrations
4. Better Patient Compliance
31. 5. Lower Adverse/Side Effects
In conventional dosage forms, the dose and dosing intervals of each drug are varied. Each
drug shows a different therapeutic response in plasma concentrations; the unbalanced
response can result in improper therapeutic effect or unwanted side effects
Generally, with rate-controlled dosage forms, the dosing intervals are increased and
fluctuations in plasma levels are decreased thereby decreasing the risk of unwanted side
effects
The occurrence of side effects is a part of drug plasma concentration and its
properties, which can be minimized by handling drug concentration in plasma at a
particular time
Example: Levodopa, when administered in the form of CRDDS, reduces the possibility of
dyskinesia caused by the drug
The CRDDS are able to reduce side effects occurring in the GIT and are known to produce
effective results
Example: the drug candidates like potassium chloride and ferrous sulfate tend to cause
irritation in the GIT, but on slowing the release of these drugs the irritant effect can be
reduced
32. Physicochemical Properties of Drug – occurrence of side effects
Different physicochemical properties of drug-like solubility, partition coefficient, and
its stability tend to affect the therapeutic responsiveness of a drug and occurrence of
side effects
Dissolution of the drug in body fluids is the first step required in the drug delivery
process; the drug molecules with low solubility in aqueous medium additionally
manifest poor bioavailability. Hence, a drug should be extensively dissolved at a
rapid dissolution rate to achieve utmost convenience in therapeutic response
Partition coefficient explains the distribution of the drug in two phases, between
the lipid phase and water phase. This property demonstrates permeation of drugs
through biological membranes and its interaction with receptors
33. The higher value of partition coefficient enables a drug to penetrate easily through
membranes but does not enable it to process further because of a lack of affinity
with aqueous surroundings
The drug candidates with low partition coefficient value show a greater affinity
towards the aqueous surroundings of the body but cannot reach the biological
membrane. So to achieve a proper distribution of drug among biological
membrane an optimum range of partition coefficient value is required
After administration of the drug into the body, the body fluids come in contact with
the drug and affect its stability. During this event, the drug is likely to face the
chemical and enzyme degradation, which can cause a reduction in
performance of the drug within the body.
The drugs that show poor stability in acidic pH can be coated with enteric
polymer materials to bypass the acidic pH effect in the stomach and can release
the drug in the lower gastrointestinal tract. The drugs can also be modified
chemically to form prodrugs, to be protected from enzymatic cleavage reactions.
Also the molecular interactions among drugs, drugs and metals, and drugs
and proteins show important factors that can bring a change in the
pharmaceutical performance of a drug candidate. These factors should be
considered while designing CRDDS
34. 6. Augmented Efficacy
While designing the ideal drug delivery system two requisites are necessary to fulfill
1. The drug should get delivered at a rate that a body requires over a period of time
2. The action should be at the specific site at specific receptors
The CRDDS can achieve these goals. These systems are capable of maintaining the drug
level in the body for the extended time period
The prolonged release dosage form slows down the absorption rate due to the slow release
rate of the drug by small bursts over time, which affects and improves the overall efficacy of
the CRDDS
The reduction in fluctuations of plasma drug concentration is desirable for constant drug
levels, which can be achieved by reducing the adverse effect and by increasing minimum
effective concentrations and thereby increasing the efficacy
35. BIOLOGICAL RATIONALE FOR CRDDS
1. Absorption
For developing a CRDDS the extent and rate of absorption of the drug are very
important factors. Drugs with a very slow rate of absorption show poor
bioavailability, which in turn makes them poor candidates to be formulated into
CRDDS
The drug candidates with more rapid absorption than release promise a
successful controlled release product formulation
Absorption window (they need transporter- mediated absorption or only
soluble at particular pH) is another factor that affects the bioavailability of orally
administered drugs and can be a hindrance to the development of conventional
drug delivery system. This is because some drugs have the property of
absorption in a specific region of the GIT, which after absorption in the
absorption window can go waste
36. Absorption efficiency differs throughout the GIT, which directly affects the extent
of drug absorption from the site. Most of the drugs are poorly soluble and poorly
permeable, thereby less absorbable. Thus, in such cases, the use of CRDDS
enables them to be carried out into the cell easily
The release of the dosage form is a rate-limiting step in case of CRDDS rather
than absorption. The amount of drug absorbed from conventional dosage forms
can be low compared with CRDDS due to various reasons like degradation or
metabolism or physical loss
For example, Pilocarpine gets absorbed across the cornea in about 1% ratio of
applied dose; the loss occurs due to drainage and absorption in nonspecific
tissue. The prepared controlled release product improves its bioavailability and
maintains a constant level of drug in specific tissue for the time required
37. 2. Drug-Protein Binding
One of the major problem with conventional dosage form is the lesser availability of the
drug in the blood due to higher protein binding. This binding decreases the action of drug
and thereby the effective therapeutic effect diminishes
But in case of CRDDS, the problem can be solved by formulating it in several carriers
which will further help in delivering the drug in required quantity at the desired site
The binding of the drug with proteins is a reversible process. With the decrease in the
concentration of the drug in the blood the drug-protein complex dissociates and leaves free
drug to maintain balance. This reversible process of drug binding maintains the drug level
in the blood for a long time. The binding of the drug with protein can function as a drug
store for generating long-term action
For example, the blood proteins keep recirculating in the body and are not eliminated; they
act as a depot for drug candidates showing controlled release profile. The quaternary
ammonium compounds have the tendency to bind with mucin in the GIT, and the drugs
that get bound to mucin act as a depot and enhance the absorption
38. 3. Distribution
The drug distribution in the body is an important criterion in determining the overall
elimination kinetics of the drug
The distribution comes with the drug binding to tissue and protein in circulation. Generally
the drug in the bound condition is termed as inactive and is not able to cross the
membranes
The high binding of the drug shows the prolonged release
For designing of the CRDDS, one needs to have knowledge of drug disposition but the fate
is usually decided on the basis of pharmacokinetic parameters such as volume of
distribution (Vd). It plays an important role as it affects the amount of drug in systemic
circulation or reaching the target. The drugs having a volume of distribution (Vd) higher
than the real volume of distribution show lesser half-life
The Vd affects the concentration of the drug in the blood also it has effects on elimination
kinetics of a drug candidate. The information on Vd allows to act as a guide for studies in
drug dosing. The distribution property of a drug is described well by Vd by either extent of
distribution in the body or by relative distribution of the drug in compartments
39. These two parameters are independent of each other, for example
The relative distribution of procainamide is almost 10 times that of pentobarbital though
the volume of distribution for both the drugs is the same
Similarly, the relative distribution for procainamide is much larger than digoxin and the
volume of distribution at steady state is lower than that of digoxin
Distribution from the conventional dosage form directly gets distributed throughout the body,
and gets accumulated to some of the off- sites, which may lead to toxicity. Such instances
can be prevented by CRDDS, which can be specific and site- targeted and thus preventing
accumulation in other sites and also helps the complete drug to be reached to the
required site
4. Elimination
The elimination of most of the drugs occurs within 20 h of administration. The zero order rate
of release is directly proportional to the rate of elimination and is given by the biological half-
lives; the drug candidate with short half-life requires frequent dosing making it desirable to be
prepared into CRDDS and the case is opposite with drugs having a long half-life
The drugs with a half-life less than 2 h and more than 8 h are not suitable for developing into
a CRDDS. For example drugs with a half-life, less than 2 h include ampicillin and penicillin
whereas drugs with half-life more than 8 h include digitoxin and digoxin
40. 5. Dose-Dependent Bioavailability
Another factor influencing the design of CRDDS is the effect of dose
Due to low bioavailability of most drugs, higher and sometimes repeated doses
are given at certain intervals of time. This leads to patient inconvenience and
most importantly the changes of missing the dose. Such problems can be
eliminated by using the CRDDS as the tool
For example, due to the dose of procainamide, it has to be administered after
every 3 h to reduce fluctuations in plasma drug level. The CRDDS of
procainamide is able to maintain plasma level for a period of about 8 h
Bioavailability is another important criterion in consideration for the formulation
of CRDDS. A drug candidate like propoxyphene whose bioavailability is dose
dependent restricts its use in CRDDS, because of the rate at which CRDDS
should be able to achieve reproducible bioavailability. It is desired that the
CRDDS formulation should be able to show around 80% of bioavailability than
that of the conventional dosage form
41. 6. Duration of Action/ Drug Residence (Half-life)
The pharmacokinetics of a drug in a steady state concentration implies that the release rate
of the drug is directly proportional to its elimination. The drugs showing linear kinetics have
a constant half-life and do not follow a change. Mostly the factors that influence the half-life
of drugs are metabolism, distribution, and elimination
Within the Therapeutic Window The duration of drug residence and the half-life of the drug
play an important role in the designing of CRDDS. Most of the drugs available in the market
show half-life of around 20 h.
The drugs having short half-life require frequent dosing to maintain drug plasma
concentrations. So, for such drugs, CRDDS are desirable. In case of higher half-life, the
CRDDS approach is not required, as it already have the ability to remain in the body for
longer periods
For example, due to the dose of procainamide, it has to be administered after every 3 h to
reduce fluctuations in plasma drug level. The CRDDS of procainamide is able to maintain
plasma level for a period of about 8 h
42. 7. Better Safety Margin
In conventional dosage form, the margin of safety is quite low compared to CRDDS, due to
accumulation at off-sites, less target specific, protein binding etc.
When it comes to safety, again the major concern comes is the elimination of the polymers
and other excipients used in the CRDDS without accumulation or side effects
The types of polymers used must be biodegradable enough so that the alternate effects of
its metabolites are less and without toxic effects
Among myriad approaches to defining the safety margin of drugs, the therapeutic index (TI)
is the most common criteria to be followed
This ratio merely provides a crude estimate of the relative safety of drugs; the drug
candidate is considered safe if the TI is in value exceeding 10. The larger the ratio is, then
safer the drug
This approach plays an important role in the monitoring of a drug therapy, especially in case
of those drug candidates that have either narrow therapeutic index or have narrow
therapeutic concentration like antiarrhythmic drugs (e.g., digoxin and digitoxin)
43. 8. Individualization in Diseased Condition
The Individualization in disease state of a body is not among drug characteristics but it is an
important part in consideration of drug candidate for CRDDS
Individualization: Patient research by themselves (if requested patients should be given
information about the purpose, harms and benefits of particular treatment)
Individual needs- From burdensome medication regimens (as in Long term treatment)
For example, aspirin is still used in RA for treatment but is not considered as a good
candidate in conventional drug delivery due to its biological half-life (6 h). Whereas a
controlled dosage form tends to maintain a therapeutic concentration and is able to provide
release up to 10 h, which is more than non-controlled formulation
The safety margin of the drug can be made out using TI of the drug along with its plasma
concentration value, to make it therapeutically effective. This approach is valuable for the
drug with a narrow absorption window and narrow therapeutic range concentration
The pattern of drug release should be precise, to achieve safe therapeutic range; also other
factors like an accumulation of drug due to frequent dosing and variability in patients can
alter plasma level. By controlling the TI is possible to control drug concentration