1. Concept & drug properties relevant to CRDDS JIJO THOMAS
M. Pharm Pharmaceutics College of Pharmaceutical Sciences
TRIVANDRUM
2. INTRODUCTION Controlled drug delivery is one which delivers
the drug at a predetermined rate, for locally or systemically, for
a specified period of time The release of drug ingredient from a
crdds proceeds at a rate profile that is not only predictable, but
also reproducible from one unit to another
3. Plasma concentration time profile
4. Advantages Total dose is low. Reduced GI side effects.
Reduced dosing frequency. Better patient acceptance and compliance.
Less fluctuation at plasma drug levels. More uniform drug effect
Improved efficacy/safety ratio.
5. Disadvantages Delay in onset of drug action Possibility of
dose dumping in the case of 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 ER dosage form
6. Classification CRDDS RATE PREPROGRAMMED DDS ACTIVATION
MODULATED DDS FEED BACK REGULATED DDS SITE TARGETING DDS
7. Rate preprogrammed DDS The release of drug molecules from
the delivery systems has been programmed at specific rate profiles.
Accomplished by system design, which controls the molecular
diffusion of drug molecules in and/ or across the barrier medium
within or surrounding the delivery system.
9. Polymer membrane permeation controlled DDS Drug formulation
is totally or partially encapsulated within a drug reservoir. Drug
release surface is covered by a rate controlling polymer membrane
having a specific permeability Drug reservoir may be in the form of
solid, suspension or in solution form The polymer membrane can be
fabricated from a non porous ( homo/hetero) polymeric material or a
micro porous membrane. Encapsulation of drug in the reservoir is
done by injection molding, spray coating, microencapsulation or
other techniques
10. The release of drug molecule from this type of system is
controlled at a programmed rate by controlling the partition
co-efficient, diffusivity, thickness of membrane. Eg. prgestasert
IUD: drug reservoir : suspension of progesterone crystals in
silicone fluid & encapsulated in T-shaped device Copolymer :
non porous membrane of ethylene vinyl acetate
11. Occusert system: Drug reservoir: thin disk of pilocaprpine
alginate complex Copolymer : ethylene vinyl acetate
12. Polymer matrix Diffusion- controlled DDS The drug reservoir
is prepared by homogeneously dispersing drug particles in a rate
controlling polymer matrix. Polymer can be lipophilic or a
hydrophilic polymer Drug dispersion can be prepared by Blending
therapeutic dose of finely ground particles with a liquid polymer
or highly viscous base polymer followed by cross linking of polymer
chains Mixing drug solids with a rubbery polymer at an elevated
temperature. Dispersion is then molded or extruded to form a drug
delivery device By dissolving drug and the polymer in common
solvent, followed by solvent evaporation at elevated
temperature
13. Release of drug molecule is controlled by Loading dose,
Polymer solubility of drug, Drug diffusivity in polymer matrix. Ex.
Nitro-Dur : Nitro-Dur is a transdermal system contains
nitroglycerin in acrylic-based polymer adhesives with a resinous
cross- linking agent to provide a continuous source of active
ingredient
14. It is designed for application on to intact skin for 24 hrs
to provide a continuous transdermal infusion of nitroglycerin at
dosage rate of 0.5 mg/cm2/day for the treatment of angina
pectoris
15. Microreservoir partition controlled DDS Fabricated by micro
dispersion of an aq. Suspension of drug using a high energy
dispersion technique in a biocompatible polymer. Depending up on
the physicochemical properties of drugs & the desired rate of
release, device can be further coated with a layer of biocompatible
polymer to modify the mechanism & rate of drug release. Drug
dispersion is then molded to form a solid medicated disk insitu on
a impermeable metallic plastic laminate, by injection molding under
instantaneous heating
16. Eg: nitro disc Reservoir: nitro glycerin suspension &
lactose triturate in aq: solution of 40% PEG Polymer: Isopropyl
palmitate Ex. Syncro mate - c It is fabricated by dispersing the
drug reservoir, which is a suspension of norgestomet in an aqueous
solution of PEG 400, in a viscous mixture of silicone
elastomer
17. Activation modulated drug delivery system Release is
activated by some physical, chemical or biochemical process. Drug
release is controlled by regulating the process applied or energy
input. Based on the process applied or type of energy used these
activation modulated DDS can be classified into
18. 1. Physical means a. Osmotic pressure-activated DDS b.
Hydrodynamic pressure-activated DDS c. Vapor pressure-activated DDS
d. Mechanically activated DDS e. Magnetically activated DDS f.
Sonophoresis activated DDS g. Iontophoresis activated DDS h.
Hydration-activated DDS 2. Chemical means a. pH- activated DDS b.
Ion- activated DDS c. Hydrolysis- activated DDS 3. Biochemical
means a. Enzyme- activated DDS b. Biochemical- activated DDS
19. Osmotic controlled activated drug delivery system In this
type, drug reservoir can be either solution or solid formulation
contained within semi permeable housing with controlled water
permeability. The drug is activated to release in solution form at
a constant rate through a special delivery orifice. The rate of
drug release is modulated by controlling the gradient of osmotic
pressure
20. Eg. Alzet Osmotic pump
21. Rate controlling factors : Water permeability of the semi
permeable membrane. Effective surface area of the semi permeable
membrane. Osmotic pressure difference across the semi permeable
membrane
22. Hydrodynamic pressure activated Drug delivery system Also
called as push-pull osmotic pump. This system is fabricated by
enclosing a collapsible, impermeable container, which contains
liquid drug formulation to form a drug reservoir compartment inside
rigid shape-retaining housing. A composite laminate of an adsorbent
layer & a swellable, hydrophilic polymer layer is
sandwiched.
23. Rate controlling factors : Fluid permeability Effective
surface area of the wall with the annular opening. Hydrodynamic
pressure gradient.
24. Vapor pressure-activated drug delivery system In this
system, the drug reservoir in a solution formulation, is contained
inside an infusate chamber. It is physically separated from the
vapor pressure chamber by a freely movable bellows. The vapor
chamber contains a vaporizable fluid, which vaporizes at body temp.
& creates a vapor pressure. Under the vapor pressure created,
the bellows moves upward & forces the drug solution in the
infusate chamber to release, through a series of flow regulators
& delivery cannula into the blood circulation at a constant
flow rate
25. Rate controlling factors : Differential vapor pressure
Formulation viscosity Size of the delivery cannula Ex. An
implantable infusion pump for the constant infusion of heparin for
anti-coagulant therapy, insulin in diabetic treatment &
morphine for patient suffering from the intensive pain of terminal
cancer
26. Mechanically activated drug delivery system In this type,
drug reservoir is in solution form retained in a container equipped
with mechanically activated pumping system. A measured dose of the
drug formulation is reproducible delivered in to a body cavity, for
ex. The nose through the spray head upon manual activation of the
drug delivery pumping system Ex. Metered-dose inhaler: the volume
of solution delivered is controllable, as small as 10-100 l &
is independent of the force & duration of the activation
applied as well as the solution volume in the container
27. Magnetically activated drug delivery system In this type,
drug reservoir is a dispersion of peptide or protein powders in
polymer matrix from which macromolecular drug can be delivered only
at a relatively slow rate. This low rate of delivery can be
improved by incorporating electromagnetically triggered vibration
mechanism into polymeric device combined with a hemispherical
design
28. Device is fabricated by positioning a tiny magnet ring in
core of hemispherical drug dispersing polymer matrix. The external
surface is coated with drug impermeable polymer (ethylene vinyl
acetate or silicon elastomer) except one cavity at the centre of
the flat surface. This delivery device used to deliver protein
drugs such as bovine serum albumin, at a low basal rate, by a
simple diffusion process under non triggering condition. As the
magnet is activated to vibrate by external electromagnetic field,
drug molecules are delivered at much higher rate
29. Sonophoresis - activated drug delivery system Also called
as Phonophoresis. This type of system utilizes ultrasonic energy to
activate or trigger the delivery of drug from polymeric drug
delivery device. System can be fabricated from nondegradable
polymer (ethylene vinyl acetate) or bioerodiable polymer
(poly[bis(p-carboxyphenoxy) alkane anhydride]
30. Iontophoresis activated drug delivery system This type of
system uses electrical current to activate & to modulate the
diffusion of charged drug across biological membrane. This system
to facilitate the percutaneous penetration of anti-inflammatory
drugs such as dexamethasone sodium phosphate to surface tissue
Iontophoresis facilitated skin permeation rate of charged molecule
(i) consist of 3 components & is expressed by, Ji sp = Jp + Je
+Jc Jp passive skin permeation flux Je electrical current driven
permeation flux
31. Hydration activated drug delivery system In this system,
the drug reservoir is homogeneously dispersed in a swellable
polymer matrix fabricated from a hydrophilic polymer (ethylene
glycomethacrylate). The release of drug is controlled by the rate
of swelling of polymer matrix
32. pH- activated drug delivery system This type of chemically
activated system permits targeting the delivery of drug only in the
region with selected pH range. It fabricated by coating the
drug-containing core with a pH sensitive polymer combination. A
gastric fluid labile drug is protected by encapsulating it inside a
polymer membrane that resist the degradative action of gastric
pH
33. In the stomach, coating membrane resists the action of
gastric fluid (pH7.5) activates the erosion of the intestinal fluid
soluble polymer from the coating membrane. This leaves a micro
porous membrane constructed from the intestinal fluid insoluble
polymer, which controls the release of drug from the core tablet.
The drug solute is thus delivered at a controlled manner in the
intestine by a combination of drug dissolution & pore-channel
diffusion
34. Ion- activated drug delivery system An ionic or a charged
drug can be delivered by this method & this system are prepared
by first complexing an ionic drug with an ion- exchange resin
containing a suitable counter ion. Ex. By forming a complex between
a cationic drug with a resin having a So3- group or between an
anionic drug with a resin having a N(CH 3)3 group. The granules of
drug-resin complex are first treated with an impregnating agent
& then coated with a water-insoluble but water permeable
polymeric membrane
35. This membrane serves as a rate- controlling barrier to
modulate the influx of ions as well as the release of drug from the
system. In an electrolyte medium, such as gastric fluid ions
diffuse into the system react with drug resin complex & trigger
the release of ionic drug. Since the GI fluid regularly maintains a
relatively constant level of ions, theoretically the delivery of
drug from this ion activated oral drug delivery system can be
maintained at a relatively constant rate
36. .Hydrolysis- activated DDS This type of system depends on
the hydrolysis process to activate the release of drug. Drug
reservoir is either encapsulated in microcapsules or homogeneously
dispersed in microspheres or nano particles for injection All these
systems prepared from bioerodible or biodegradable polymers
(polyanhydride, polyorthoesters). It is activated by
hydrolysis-induced degradation of polymer chain & is controlled
by rate of polymer degradation.
37. Ex. LHRH releasing biodegradable subdermal implant, which
is designed to deliver goserline, a synthetic LHRH(Luteinizing
hormone-releasing hormone) analog for once a month treatment of
prostate carcinoma
38. Enzyme - activated drug delivery system This type of
biochemical system depends on the enzymatic process to activate the
release of drug. Drug reservoir is either physically entrapped in
microspheres or chemically bound to polymer chains from biopolymers
(albumins or polypeptides). The release of drug is activated by
enzymatic hydrolysis of biopolymers (albumins or polypeptides) by
specific enzyme in target tissue. Ex. Albumin microspheres release
5
39. Feedback regulated drug delivery system In this group the
release of drug molecules from the delivery system is activated by
a triggering agent. Rate of drug release is controlled by
concentration of triggering agent
40. Bioerosion-regulated drug delivery system The system
consisted of drug-dispersed bioerodible matrix fabricated from poly
(vinyl methyl ether) ester which is coated with layer of
immobilized urease
41. In a solution with near neutral pH, the polymer only erodes
very slowly. In presence of urea, urease metabolizes urea to form
ammonia. This causes increase in pH & rapid degradation of
polymer with release of drug molecule
42. Bioresponsive drug delivery system Drug reservoir is
contained in device enclosed by bioresponsive polymeric membrane
whose drug permeability is controlled by concentration of
biochemical agent
43. Eg glucose-triggered insulin drug delivery system
44. In this system, the insulin reservoir is encapsulated
within hydro gel membrane having NR2 group. In alkaline solution,
the NR2 are neutral & the membrane is unswollen &
impermeable to insulin. Glucose penetrates into the membrane, it
oxidizes enzymatically by the glucose oxidase entrapped in the
membrane to form gluconic acid. The NR2 group is protonated to form
NR2H+ & the hydro gel membrane then becomes swollen &
permeable to insulin molecules
45. Self-regulating drug delivery system This type of system
depends on a reversible & competitive binding mechanism to
activate and to regulate the release of drug. Drug reservoir is
drug complex encapsulated within a semi permeable polymeric
membrane. The release of drug from the delivery system is activated
by the membrane permeation of biochemical agent from the tissue in
which the system is located.
46. Ex. In the complex of glycosylated insulin concanavalin A,
which is encapsulated inside a polymer membrane. Glucose penetrates
into the system & it activates the release of glycosylated
insulin from the complex for controlled delivery out of
system.
47. Site targeting drug delivery system
48. FACTORS INFLUENCING THE DESIGN OF CONTROLLED RELEASE DRUG
DELIVERY SYSTEMS
49. Factors influencing the release of drug delivery systems
include: Physicochemical properties of the drug : o Aqueous
solubility o Partition coefficient o Molecular size o Drug
stability o Protein binding Physiological factors: o Absorption
Distribution o Metabolism o Elimination o Duration of action o
Margin of safety o Disease state Other factors o Target site o The
patient conditions
50. Solubility Drugs having low aqueous solubility suffer from
low bioavailability Solubility of some drugs depends on the pH,
which varies throughout the GIT and leads to uneven and erratic
absorption. Drug release from controlled release systems are
designed by considering the drug solubility. Diffusional systems
are poor choice for poorly soluble drugs
51. Partition coefficient and molecular size Partition
coefficient is an important property that governs the permeation of
drug particles through biological membrane and diffusion of drug
molecules across rate controlling membrane Drugs with low partition
coefficient value easily permeate through biological membrane The
ability of the drug to diffuse through the membrane is called
diffusivity and this depends on the molecular size. Molecular size
is indirectly proportional to molecular size
52. Drug stability Stability of the drug in the environment to
which it is exposed is another physicochemical factor to be
considered in the design of controlled release systems. Drugs that
are unstable in stomach can be placed in a slowly soluble form or
have their release delay until they reach the stomach. Drugs that
undergo gut-wall metabolism and that show instability in small
intestine are not suitable for controlled release
53. Protein binding : Duration of action is a function of
protein binding. Drug protein binding can serve as a depot for drug
producing a prolonged release profile, especially if drug binding
occurs. However other protein-drug interactions have a negative
influence on drug performance. However if degradation or washing of
the drug in the GI tract occurs, binding of drug to mucin may
result in reduction of free drug available for absorption
54. Absorption Absorption controlled drug delivery system
should release complete drug and then released drug should
completely absorbed. The uniform drug absorption though incomplete
may lead to successful design of oral controlled release drug
delivery systems. The variation in absorptive characteristics of
different segments of the GIT will influence the design of
controlled drug
55. Distribution The distribution of drug molecule into the
tissues and cells can be a primordial factor in and drug
elimination kinetics. Distribution includes the binding of drugs to
the tissues and blood proteins Apparent volume of distribution is
an important parameter that describes the magnitude of distribution
as well as protein binding in the body. Vd = (amount of drug in
body) / (plasma drug concentration)
56. Metabolism It is either inactivation of a drug or
conversion of an inactive drug to an active metabolite. Complex
metabolic patterns make the designing of controlled release system
more complicated, Two main factors related to metabolism restrict
the design of sustained or controlled drug delivery. Drugs which
are administered for a long period that is capable of inducing or
inhibiting enzyme synthesis.These drugs are poor candidates for
sustained release formulations. Drugs which have variations in
bioavailability due to first pass metabolism or intestinal
metabolism are not suitable.
57. Duration of action The duration of action influences the
controlled release formulations and is dependent on the biological
half life of the drug. Usually drugs with short half life require
frequent dosing to minimise the fluctuations in the blood
concentrations. Such types of drugs are more suitable for
controlled release drug delivery systems.
58. Side effects Side effects of drugs are mainly due to the
fluctuations in the plasma concentration of drug This can be
minimised by controlling the concentration within the therapeutic
range at any given time.
59. Margin of safety Toxicity can be prevented by considering
the therapeutic index which is the ratio of median toxic dose and
median effective dose. Drugs with large therapeutic index are safer
drugs. TI = TD 50 / ED 50 In general drugs with a TI more than 10
is considered to be relatively safe
60. Disease state The disease state of an individual is
sometimes considered before formulation of controlled release
systems. Aspirin is the choice of drug for rheumatoid arthritis but
is not a suitable candidate for sustained release oral dosage
forms. Some disease states are influenced by the circadian rhythms
eg : acute myocardial insufficiency
61. Circadian rhythm Liver enzyme activity, blood pressure and
intraocular pressure etc follows a circadian rhythm. As a result
the response to certain drugs also follows a circadian rhythm. This
include digitalis glycosides, diuretics and psychoactive drugs like
amphetamine, barbiturates, carbamazepines
62. Effects of system parameters on controlled release drug
delivery Polymer & Solution Solubility Polymer & Solution
Diffusivity Thickness of polymer diffusion path & hydro-
dynamic layer Partition Co-efficient Surface Area Loading Dose
63. Polymer Solubility For drug to be release, the drug
molecules on the outmost surface must dissociate from its crystal
lattice structure, partition or dissolve in surrounding medium. As
the solubility of drug particles in rate controlling membrane and
polymer matrix plays rate-controlling role in release from a
polymeric device. To release at an appropriate rate the drug should
have adequate polymer solubility. Rate of drug release is directly
proportional to magnitude of polymer solubility
64. Solution Solubility Aqueous solubility varies from one drug
to another. Difference in aqueous solubility is depend on the
difference in their chemical structure, types & physicochemical
nature of functional groups & the variations in their stereo
chemical configurations Drug release increases with increase in
Solution solubility of drug.
65. Partition Coefficient Partition co-efficient K of a drug
for it s interfacial partitioning from the surface of a drug
delivery device towards an elution medium as given : K = C s /C p
Where, C s = conc. Of drug at the solution/polymer interface C p =
solubility of drug in the polymer phase
66. Any variation in either C s or C p result in increase or
decrease in magnitude of K value. Rate of drug release increase
with increase in partition coefficient
67. Polymer Diffusivity The diffusion of small molecules in a
polymer structure is a energy activated process in which the
diffusant molecules move to a successive series of equilibrium
positions when a sufficient amount of energy of activation for
diffusion E d , has been acquired by the diffusant & it s
surrounding polymer matrix
68. Magnitude of polymer diffusivity is dependent upon type of
functional group and type of stereo chemical position in diffusant
molecule. The bulkier the functional group attached to polymer
chain lower the polymer diffusivity. Polymer diffusivity also
depends on , 1) Effect of cross linking (inverse relationship) 2)
Effect of crystallinity (inverse relationship) 3) Effect of
fillers
69. Solution Diffusivity The diffusion of solute molecules in
solution medium is a result of the random motion of molecules.
Under concentration gradient molecule diffuse spontaneously from
higher concentration to lower concentration. Diffusivity of solute
molecule in aqueous solution usually decreases as its concentration
increases
70. Thickness of hydrodynamic diffusion layer The rate limiting
role of the hydrodynamic diffusion layer on drug release profile
can be explained by considering that as a device immersed in a
solution, a stagnant layer is formed on the immediate surface of
device The drug release profile is a function of variation in the
thickness of hydrodynamic diffusion layer on the surface of matrix
type drug delivery device The magnitude of Q/t decreases as the
thickness of hydrodynamic diffusion layer is increased
71. Drug loading dose Any intension to prolong the duration of
medication by incorporating a higher loading dose of a therapeutic
agent into a matrix type drug delivery device produces a greater
value for drug release flux Rate of drug release from a membrane
permeation controlled reservoir type device is independent of
loading dose
72. Surface Area Greater the surface area greater will be the
rate of drug release
73. References 1. Novel drug delivery system- Y.W.Chien. Pg no.
1- 132 2. Biopharmaceutics & pharmacokineticsBrahmankar. Pg no.
335 - 370 3. Fundamentals of controlled release drug delivery-
Robinson. Pg no. 3-61,482 - 500 4. Controlled drug delivery systems
by: S P Vyas
