Concept & drug properties relevant to crdds

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.

8. Rate preprogrammed
Rate
preprogrammed
DDS
Polymer membrane
controlled DDS
Polymer membrane
diffusion controlled
DDS
Micro reservoir
partition controlled
DDS

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

26. 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

27. 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 µl & is independent of the force &
duration of the activation applied as well as
the solution volume in the container

28. 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

30. • 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

31. 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]

33. 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

34. 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

35. 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

37. • In the stomach, coating membrane resists the
action of gastric fluid (pH<3) & the drug molecule
thus protected from acid degradation.
• After gastric emptying the DDS travels to the small
intestine & intestinal fluid (pH>7.5) 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

38. 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

40. • 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

41. .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.

42. 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

43. 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 –

44. 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

45. 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

46. • 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

47. 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

48. Eg– glucose-triggered insulin drug delivery
system

49. • 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

50. 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.

51. 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.

52. Site targeting drug delivery
system

53. FACTORS INFLUENCING THE
DESIGN OF CONTROLLED
RELEASE DRUG DELIVERY
SYSTEMS

54. 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

55. 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

56. 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

57. 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

58. 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

59. 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

60. 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)

61. 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.

62. 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.

63. 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.

64. 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

65. 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

66. 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

67. 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

68. 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

69. 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.

70. 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

71. • 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

72. 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

73. • 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

74. 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

75. 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 ½ decreases as the
thickness of hydrodynamic diffusion layer is
increased

76. 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

77. Surface Area
Greater the surface area greater will be the rate
of drug release

78. 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