Controlled Drug delivery System

1. BY
MOHAMMAD ALI
ASSISTANT PROFESSOR
BHARATHI COLLEGE OF PHARMACY
BHARATHINAGARA - 571422

2. INTRODUCTION
DRUG DELIVERY SYSTEM
Is a formulation or device that delivers the drug in site-
directed application or provides timely release of the
drug.
The system, is not pharmaceutically active, but
improves the efficacy and safety of the Drug that it
carries.
Controlled drug delivery can be achieved by;
1. SPACIAL PLACEMENT
2. TEMOPORAL DELIVERY

3. INTRODUCTION
IDEAL CHARACTERISTICS OF DRUG DELIVERY:
 Reduce drug toxicity
 Increase the absorption of a n insoluble drug.
 Improve the drug release profile.
 Create truly best-in-class products.
 Reduce price.
 Control the drug release.
 The ability to target.

4. TERMINOLOGY
1. Delayed Release:
Delayed release systems are those that use repetitive,
intermittent dosing of drug from one or more
immediate release units incorporated into a single
dosage form.
E.g., Repeat action tablet, Enteric coated tablet
2. Sustained Release:
Sustained release systems include any drug delivery
system that achieves slow release of drug over
extended period of time.
E.g., Zenretard SR (Carbamazepine)

5. 3. Site specific and Receptor Targeting:
Site specific and receptor targeting refers to targeting
of a drug delivery to a certain biological location.
CONTROLLED DELIVERY CAN BE DEFINED AS:
CDDS is the one which delivers the drug at a
predetermined rate, locally or systemically, for a
specific period of time.
TERMINOLOGY

6. Conventional Drug Therapy

7. Multi Dose Therapy

8. Controlled Release System

9. Avoid patient compliance problems.
Employ less total drug.
Improve efficiency in treatment.
Economic.
Reduced GI side effects and irritation.
Increased safety margin of high potency drugs.
ADVANTAGES

10. Dose dumping.
Poor in vitro – in vivo correlation.
Dose adjustment is difficult.
Retrieval of drug is difficult once administered.
Chance of incomplete release of drug from the
device.
DISADVANTAGES

11. In general the drugs best suited for CDDS products should
have the following characteristics.
 They exhibit neither very slow nor very fast rates of
absorption and excretion.
 They are uniformly absorbed from the GI Tract.
 They are administered in relatively small doses. Drugs with
a dose of <100 mg.
 Drugs with a half life of 3-6 hrs and specifically defined
minimum therapeutic levels.
 Drugs that possess a good margin of safety
 Drugs with low protein binding properties.
 They are used in the treatment of chronic rather than acute
condition
SELECTION OF DRUG CANDIDATE

12. Drugs with an elimination half life of < 2 hrs.
Drugs with an elimination half life of >8 hrs.
Drugs that are administered in large doses.
Highly potent drugs. They may prove risky in case
of dose dumping.
DRUG CANDIDATE UNSUITABLE
FOR CDDS

13. RATIONALE AND SELECTION OF
DRUG CANDIDATE

14.  Various factors that effect the design and performance
of OCDDS are listed below:
(a) Physico-chemical property
(i) Aqueous solubility
(ii) Molecular weight of the drug
(iii) Partition co-efficient of the drug
(iv) Drug pKa and ionization at physiologic pH.
(v) Drug stability
RATIONALE AND SELECTION OF
DRUG CANDIDATE

15. (b) Biological factors
(i) Adsorption
(ii) Metabolism
(iii) Elimination half life
(iv) Dosage form index
(c) Pharmacodynamic factors
(i) Therapeutic Index

16.  The design and fabrication of controlled release system
can be classified based on the mechanism of drug
release.
1. Dissolution controlled release.
2. Diffusion controlled release.
3. Diffusion and dissolution controlled release.
4. Ion exchange resins.
5. pH dependent formulations.
6. Osmotically controlled release
7. Altered density formulation/Buoyant systems.
APPROACHES TO DESIGN OF
CONTROLLED RELEASE FORMULATIONS

17.  These system are easy to design.
 In this system solid substances solubilize in a given
solvent (dissolution).
 i.e., Mass transfer form solid surface to the liquid phase.
 The rate determining step, is diffusion of the soluble
solute from the solid surface to the bulk of the solution
through stagnant layer.
 This dissolution process at steady state is described by
the Noyes and Whitey equation.
DISSOLUTION CONTROLLED
RELEASE SYSTEMS

18. Noyes – Whitney Law
 Solution of the solid to form a thin film at S/L interface
called Stagnant film. Which gets saturated with the drug
(Rapid)
 Diffusion of the soluble solute from the stagnant layer to
the bulk solution (Rate Determine Step)

19. 𝑑𝐶
𝑑𝑡
= kDA(Cs−C)=
𝐷
ℎ
A (Cs−C)
Where,
𝑑𝐶
𝑑𝑡
= Dissolution rate
kD= Dissolution rate constant
D = Diffusion coefficient
Cs= Saturation solubility of the solid
C = Concentration of solute in the bulk sol.
A = Surface area of the exposed solid
Noyes – Whitney Equation

20. Here, the formulation are designed in such a way that it
can decrease the rate of dissolution of the drug.
This can be achieve by preparing appropriate salts or
derivatives, coating the drug with a slowly dissolving
material, or incorporating it into a tablet with a slowly
dissolving carrier.
DISSOLUTION CONTROLLED
RELEASE SYSTEMS

21. Classification:
• The two types of dissolution controlled release systems
are:
(a) Matrix/Monolith dissolution controlled system.
(b) Encapsulation/coating dissolution controlled
system/reservoir devices.
DISSOLUTION CONTROLLED
RELEASE SYSTEMS

22. (a) Matrix/Monolith Dissolution Controlled System:
The drug is homogeneously dispersed throughout a
rate controlling medium.
Use of waxes such as beeswax, carnauba wax,
Hydrogenated castor oil, etc.
These things control drug dissolution by controlling
the rate of dissolution (fluid penetration) into the
matrix by:
1. Altering porosity of tablet
2. Decreasing its wettability
3. Dissolving at slower rate.
DISSOLUTION CONTROLLED
RELEASE SYSTEMS

23. Slowly Dissolving
Matrix
DISSOLUTION CONTROLLED
RELEASE SYSTEMS
Soluble Drug
Drug release determined by dissolution rate of polymer

24.  Preparation Method:
Prepared by dispersing the drug in molten wax and
congealing (solidify).
The drug release is often first order from such matrices.
DISSOLUTION CONTROLLED
RELEASE SYSTEMS
Molten
Wax
Drug
Mix
Solidify
Granulation

25. (b) Encapsulation/Coating Dissolution Controlled
System/Reservoir Devices:
 Here the drug particles are coated or encapsulated with
slowly dissolving materials like, cellulose, poly ethylene
glycol (PEGs), Polymethacrylates, waxes etc.
 Dissolution rate of coat depends upon solubility and
thickness of coating which may range from 1-200μ.
DISSOLUTION CONTROLLED
RELEASE SYSTEMS
Soluble Drug
Slowly dissolving
or Erodible coat

26.  Applications:
Masks Colour, Odour and Taste.
Minimizes GI irritation.
The pellets may be filled in Hard gelatin capsules.
It may be compressed into tablets.
DISSOLUTION CONTROLLED
RELEASE SYSTEMS

27.  The rate-controlling step is not the dissolution rate but the
diffusion of dissolved drug through a polymer barrier.
 Usually, this barriers is an insoluble polymer.
 The process of diffusion is generally described by Fick’s
first Law.
 This states that “the amount of drug passing across a unit
area is proportional to the concentration difference across
the plane”
DIFFUSION CONTROLLED RELEASE
SYSTEMS

28.  The equation is given as:
𝐽 = −𝐷
𝑑𝐶
𝑑𝑋
 Where, J = Flux
D = Diffusion coefficient of the drug in the
membrane
𝑑𝐶
𝑑𝑋
= The rate of change in concentration C relative
to a distance X in the membrane
• The drug release rate is never zero order since the diffusional path length
increases with time as the insoluble matrix is gradually depleted of drug.
DIFFUSION CONTROLLED RELEASE
SYSTEMS

29.  Classification:
The two types of diffusion controlled Systems are:
(a) Matrix diffusion controlled systems.
(b) Reservoir devices/laminated matrix devices.
(a)Matrix Diffusion Controlled Systems:
It consists of drug dispersed homogeneously
throughout a polymer matrix.
This polymer matrix may be rigid, non-swellable.
It consists of hydrophobic materials or swellable
hydrophilic substances.
DIFFUSION CONTROLLED RELEASE
SYSTEMS

30. Polymer used in Matrix diffusion controlled system
Rigid Matrix
Insoluble Plastics
E.g., Polyvinyl
Chloride
Fatty materials
E.g., Stearic acid,
Bees Wax
Swellable Matrix
Hydrophilic gums
Natural Gums
E.g., Guar gum,
Tragacanth
Semisynthetic
Gums
E.g., HPMC, CMC,
Xanthum gum
Synthetic
E.g., Polyacrylamide
DIFFUSION CONTROLLED RELEASE SYSTEMS
Fig: Polymer Used

31.  Preparation Method:
Method 1: With plastic materials, the drug is generally
kneaded with the solution of PVC in an organic solvent
and granulation.
Method 2: Waxy matrix is prepared by dispersing the
drug in molten fat followed by congealing and
granulation.
Method 3: Gum and the drug are granulated together
with a solvent such as alcohol and compressed into
tablets.
DIFFUSION CONTROLLED RELEASE
SYSTEMS

32.  Rate Controlling Step:
Diffusion of dissolved drug through the matrix.
DIFFUSION CONTROLLED RELEASE
SYSTEMS
Time = 0 Time = t
(a) Rigid Matrix
Polymer
Drug

33. DIFFUSION CONTROLLED RELEASE
SYSTEMS
(b) Swellable Matrix
Swollen glassy hydrogel
From which drug has to
completely diffuse
Swellable gum matrix
Drug
Fig: Diffusion Controlled Devices

34. (b) Reservoir Devices/Laminated Matrix Devices:
 Reservoir devices are characterized by a core of drug, the
reservoir, surrounded by a polymeric membrane.
 The nature of the membrane determines the rate of drug
release from the system.
 Technique used to apply polymer is coating or
microencapsulation.
 Drug release mechanism involves partitioning of drug into
the membrane with subsequent release into the
surrounding.
 The polymer commonly used in such devices are:
• HPC
• EC and PVA
DIFFUSION CONTROLLED RELEASE
SYSTEMS

35.  Rate controlling step:
Polymer content in coating, thickness of the coating
and hardness of microcapsule.
DIFFUSION CONTROLLED RELEASE
SYSTEMS
Drug
Polymer
Time = 0 Time = t
Fig: Drug Release by Diffusion across the Insoluble Membrane of Reservoir Device

36. In such systems, the drug is encased in a partially
soluble membrane.
Pores are thus created due to dissolution of parts of
membrane, that permits entry of aqueous medium.
At the same time it allows diffusion of dissolved drug
out of the system.
E.g., such can be obtaining by using mixture of EC and
PVP or MC.
Later it dissolves in water which create pores in the
insoluble EC membrane.
DISSOLUTION AND DIFFUSION
CONTROLLED RELEASE SYSTEMS

37.  Rate controlling factor:
Fraction of soluble polymer in the coat.
DISSOLUTION AND DIFFUSION
CONTROLLED RELEASE SYSTEMS
Drug
Drug diffusion
Entry of dissolution
fluid
Insoluble membrane
Fig: Dissolution and Diffusion Controlled Release System

38. It is based on the formation of drug resin complex
formed when ionic solution is kept in contact with
ionic resins.
Provides CR of an ionic or ionizable drug for intra-
gastric delivery.
The drug release rely only on the ionic environment
of the resin containing drug.
Drug is less susceptible to environmental conditions,
such as enzyme content and pH at the site of
absorption.
ION EXCHANGE RESIN DRUG
COMPLEXES

39.  Method of Preparation:
Prepared by absorbing an ionized drug onto the ion-
exchange resin granules, such as codeine base with
amberlite, and filtering through an alcoholic medium.
Then coating the drug resin complex granules with a
water permeable polymer.
Spray dry the coated granules to produce coated drug
resin preparation.
E.g., Noscapine, Phenylpropanolamine, Phentermine
have been retarded by such an approach.
ION EXCHANGE RESIN DRUG
COMPLEXES

40. ION EXCHANGE RESIN DRUG
COMPLEXES
Drug-Ion Exchange
Resin granules
Polymer coating

41.  Further Improvement of this system can be done by
treating the granules with impregnating agent like
PEG-4000
 This will retard the rate of swelling in water and then
coated by air suspension technique with water
permeable polymer (EC).
 That will act as a rate controlling barrier to regulate the
release of drug from the system.
 This further improvement of the system is known as
pennkinetic system.
ION EXCHANGE RESIN DRUG
COMPLEXES

42. ION EXCHANGE RESIN DRUG
COMPLEXES
Drug-Ion Exchange
Resin granules
Ethyl Cellulose Coating
PEG Treatment
Fig: Pennkinetic System of Ion Exchange Resin

43.  Mechanism of drug release from the dosage Form:
Cationic drugs: A cationic drug forms a complex with
an anionic ion-exchange resin.
E.g., A resin with a SO3
- group.
In GIT, H+ ion penetrates the system and activates the
release of cationic drug form the drug-resin complex.
Resin- - Drug+ + Y+ → Resin- - Y+ +Drug+
ION EXCHANGE RESIN DRUG
COMPLEXES

44.  Mechanism of drug release from the dosage Form:
Anionic drugs: A anionic drug forms a complex with an
cationic ion-exchange resin.
E.g., A resin with a [N(CH3)3
+]group.
In GIT, Cl- ion penetrates the system and activates the
release of anionic drug form the drug-resin complex.
Resin+ - Drug- + X- → Resin+ - X- +Drug-
ION EXCHANGE RESIN DRUG
COMPLEXES

45.  Advantages:
The rate of drug release is not dependent upon the pH
condition, enzyme, temperature and volume of GIT.
The system is administered in the form of large
number of particles which may eliminate the effect of
gastric emptying.
Can be formulated as a stable liquid suspension type of
pharmaceutical dosage form.
By combining different ratios of polymer coated and
uncoated granules, in the formulation, a range of
dissolution profile and blood levels can be achieved.
ION EXCHANGE RESIN DRUG
COMPLEXES