Fundamentals of controlled drug delivery system

1. By
Dr. Chinmaya Keshari Sahoo. M.Pharm, Ph.D
Associate Professor
College of Pharmaceutical Sciences, Puri

2. CONTENTS
1. Introduction
2. Modified Release Drug Delivery System (MRDDS)
3. Terminology/definitions
4. Rationale of CDDS
5. Advantages
6. Disadvantages
7. Selection of drug candidates
8. Physiological properties for CDDS
9. Biological properties for CDDS
2

3. INTRODUCTION
 Conventional oral drug delivery system offers an
immediate release of the drug and cannot maintain
effective concentration at the target site for longer
period of time.
 The bioavailability of drugs by conventional drug
delivery is less due to presence of food, pH of gastro
intestinal tract (GIT), degradation by enzymes of GI
fluid, change in GI motility etc.
 Most conventional oral drug products result in drug
absorption problem and decline drug’s pharmacokinetic
profile.
 For avoid these limitations modified release drug
delivery system has taken major role in the
pharmaceutical development.
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4. Modified release drug delivery system
Modified release drug delivery system (MRDDS)
MRDDS is defined as one for which the drug release
characteristics of time course and location are chosen to
accomplish therapeutic or convenience objectives to
influence the release profile of a drug from its delivery
system.
Classification of MRDDS
MRDDS is classified into 3 types such as
1.Extended release dosage form
2.Delayed release dosage form
3.Targeted release dosage form
4

5. Contd.
1. Extended release dosage form (ERDF)
 ERDF allows at least a twofold reduction in dosage
frequency as compared to that drug presented as an
immediate release (conventional) dosage form.
 The dosage form releases the drug slower than normal
manner at predetermined rate.
The prolonged action drug product is designed to release
the drug slowly and to provide a continuous supply of
drug over an extended period.
ERDF includes sustained release, and controlled-
release dosage forms.
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6. Contd.
 Sustained release dosage forms
 Sustained release system delivers an initial therapeutic
dose of the drug (loading dose) followed by slower and
constant release of drug.
Loading dose is an initial higher dose of a drug that
may be given at the beginning of a course of treatment
before dropping down to a lower mainteince dose.
These systems maintain the rate of drug release over a
sustained period.
Sustained-release dosage forms achieve this mostly by
the use of suitable polymers, which are used either to
coat granules or tablets (reservoir systems) or to form a
matrix in which the drug is dissolved or dispersed
(matrix systems).
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7. Contd.
 Controlled-release dosage forms
 Controlled release dosage forms cover a wide range of
prolonged action formulations which provide
continuous release of their active ingredients at
predetermined rate and predetermined time.
There is maximum utilization of drug enabling
reduction in total amount of dose administered and
possibility of delivering drugs having short biological
half life.
The release kinetics is usually follow zero-order.
Controlled drug delivery system (CDDS) can improve
the therapeutic efficacy and safety of a drug by precise
temporal and spatial placement in the body thereby
reducing both the size and number of doses required.
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8. Contd.
 Temporal delivery of drug refers to controlling the rate
or specific time of drug delivery to the target tissue.
 Spatial delivery of drugs relates to target a drug to a
specific organ or tissue.
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9. Contd.
2. Delayed release dosage form (DRDF)
 DRDF can be defined as systems which are formulated
to release the active ingredient at a time other than
immediately after administration.
 DRDF can control where the drug is released, e.g.
when the dosage form reaches the small intestine
(enteric-coated dosage forms) or the colon (colon-
specific dosage forms).
3. Targeted release dosage forms
 Targeted release dosage forms release drug at or near
the intended physiologic site of action.
 It may have either immediate or extended release
characteristics.
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10. TERMINOLOGY
1. Temporal release
2. Spatial release
3. Loading dose
4. Maintenance dose
5. Sustained release
6. Controlled release
7. Delayed release
8. Targeted release
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11. Rationale of CDDS
 The basic rationale of a CDDS is to optimize the
biopharmaceutics, pharmacokinetics (PK), and
pharmacodynamics (PD) properties of a drug in such a way that
its utility is maximized through reduction in side effects and cure
or control of disease condition in the shortest possible time by
using smallest quantity of drug, administered by most suitable
route.
 Alter PK/PD by:
– Design of drug delivery system
– Modify drug structure
– Modify physiology
 Duration of drug action is a design property of the rate
controlled dosage form and not a property of the drug molecule’s
inherent kinetic characteristics.
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12. ADVANTAGES OF CDDS
1. The frequency of drug administration is reduced.
2. Patient compliance can be improved.
3. The drug administration is more convenient.
4. There is better control of drug absorption.
5. The total amount of drug administration can be reduced.
6. Safety margin of high potency drugs can be increased.
7. Treatment efficacy is improved.
8. Bioavailability of drugs is improved.
9. Reduction in health care cost by improved therapy and
shorter treatment period.
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13. DISADVANTAGES OF CDDS
1. Poor in vitro – in vivo correlation is observed.
2.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.
3. Retrieval of drug is difficult in case of toxicity, poisoning
or hypersensitivity reactions.
4. Increased cost of manufacturing.
5.More rapid development of tolerance and counseling.
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14. SELECTION OF DRUG CANDIDATES
I. Biopharmaceutic Properties
Properties of drug Desired features
Molecular size Less than 600 D
Aqueous solubility More than 0.1 mg/ml
Partition coefficient (Ko/w) 1-2
Dissociation constant pKa Acidic drugs pKa ˃2.5,
Basic drugs pKa ˂11
Ionisation at physiological pH Not more than 95%
Stability in GI milieu Stable at both gastric and intestinal pH
Absorption mechanism Passive absorption
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15. Contd.
II. Pharmacokinetic (PK) Properties
Properties of drug Desired features
Absorption rate constant (Ka) High
Elimination half life 2-6 h
Metabolism rate Not too high
Dosage form index 1
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16. Contd.
III. Pharmacodynamic (PD) Properties
Properties of drug Desired features
Dose Maximum 1000 mg
Therapeutic range Wide
Therapeutic index Wide
PK/PD relation ship Good
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17. PHYSIOCHEMICAL PROPERTIES OF DRUG FOR CDDS
1. Aqueous solubility of the drug
2. Partition coefficient (Ko/w)
3. Drug pKa and ionization at physiological pH
4. Drug stability
5. Molecular weight of drug and diffusivity
6.Dose size
7. Protein binding
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18. CONTD.
1. Aqueous solubility of the drug
 A drug with good aqueous solubility, especially if pH
independent, serves as a good candidates
Generally highly soluble drugs are undesirable for
formulation in a controlled release product and very
poorly soluble drugs are not suitable for controlled
release system.
Class III (High solubility-low permeability) and Class IV
(low solubility-low permeability) drugs are poor
candidate for controlled release dosage forms.
The drug with solubility <0.1 mg/ml create significant
solubilization problem (Lower limit).
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19. CONTD
2. Partition coefficient (Ko/w)
Partition coefficient is defined as the fraction of drug in an
oil phase to that of an adjacent aqueous phase at
equilibrium.
Drugs with extremely high partition coefficient are very oil
soluble and penetrates in to various membranes very easily.
Greater the partition coefficient of a drug greater its
lipophilicity and thus greater is its rate and extent of
absorption.
High partition coefficient compound are predominantly lipid
soluble and have very low aqueous solubility and thus these
compound persist in the body for long periods.
 Ko/w value between 1 -2 is suitable for CDDS
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20. CONTD.
3. Drug pKa and ionization at physiological pH
Drugs existing largely in ionized form are poor
candidates for oral CDDS.
The pKa range for acidic drug whose ionization
is pH sensitive is around 3.0-7.5 and pKa range
for basic drug whose ionization is pH sensitive is
around 7.0-11.0 are ideal for optimum positive
absorption.
For optimum passive absorption the drugs
should be non ionized.
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21. CONTD.
4. Drug stability
Drugs unstable in gastrointestinal environment
cannot be administered as oral controlled release
formulation because of bioavailability problems.
A different route can be selected if failed in one
route.
Drugs stable in stomach gets released in stomach
and which are unstable gets released in intestine.
Drugs may be protected from enzymatic degradation
by incorporation in to a polymeric matrix
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22. CONTD
5. Molecular weight of drug and diffusivity
The ability of a drug to diffuse through
membranes is called diffusivity which is a
function of molecular weight.
Lower the molecular weight faster and more
complete absorption.
Drugs with large molecular size are poor
candidates for oral controlled drug delivery
system.
The upper limit of drug molecular size for
passive diffusion is 600 Daltons.
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23. CONTD
6.Dose size
For those drugs requiring large conventional doses, the
volume of sustained dose may be too large to be
practical.
 The compounds that require large dose are given in
multiple amounts or formulated into liquid systems.
The greater the dose size, greater the fluctuation.
 So the dose should have proper size.
The upper limit of dose size is 1000 mg for CDDS.
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24. CONTD.
7. Protein binding
 Drug protein binding acts as depot for drug producing
prolonged release profile-high degree of binding occurs .
 drugs + mucin= increases absorption
 Charged compounds greater tendency to bind.
e.g. Diazepam and novobiocin- 95% protein binding
Extensive binding to plasma proteins –long half life of
elimination for drugs- most required property for a sustained
release.
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25. BIOLOGICAL PROPERTIES OF DRUGS
1. Absorption
2. Distribution
3. Metabolism
4. Duration of action
5. Margin of safety
6. Role of disease state
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26. CONTD.
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27. CONTD.
1. Absorption
 Ideal CRDDS should release the complete drug and the
released drug should be completely absorbed
Drugs with poor absorption –poor candidate for CDDS.
 The fraction of drug absorbed from the system can be
lower than the expected due to:
-degradation of drug. Eg- Penicillin G
-site-specific, dose-dependent absorption,
-poor water solubility
-small partition coefficient.
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28. CONTD.
2.Distribution
 Distribution refers to the reversible transfer of drug from
one location to another inside the body.
 Depends on affinity of drug to bind with plasma proteins
and ability of drug to pass through tissue membranes.
 Apparent volume of distribution (Vd) is defined as the
hypothetical volume of body fluids to which a drug is
dissolved or distributed.
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29. CONTD.
3.Metabolism
 The drug which is extensively metabolized is suitable for
CDDS as long as the rate of metabolism is not too rapid.
 The extent of metabolism should be identical and
predictable when the drug is administered by different
routes.
 The drug which is capable of inducing or inhibiting
metabolism is a poor candidate for CDDS.
 Drugs possessing variations in bioavailability due to
first-pass effect or intestinal metabolism are not suitable for
sustained/controlled drug delivery.
 Elimination constant or appearance of metabolites –reflects
the Metabolism of a drug.
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30. CONTD.
4.Duration of action
 The usual goal – maintain therapeutic blood
levels to an extended period.
Rate of absorption= Rate of elimination
 Half life of drug range between 2- 6 h.
Short half life dose size will increase for large
release if CDDS produced.
Long half lives more than 6h sustained effect is
already there.
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31. CONTD.
5. Margin of Safety
Estimation of relative safety of drug by therapeutic index.
Therapeutic index(TI) = TD50/ED50
Where TD50 is toxic dose, ED50 is effective dose
Larger the ratio- safer the drug TI> 10
Decisions on the margin of safety is done based on the
combination with therapeutically safe and effective plasma
concentration.
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32. CONTD.
6. Role of Disease state
Disease acts as a stimulus for the development of CDDS
Example: Rheumatoid arthritis- Aspirin
 Biological half life- 6h
 Aspirin sustained release preparation –prevents morning
stiffness.
It can be sustained upto 8-10 h
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33. THANK YOU
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