Rate controlled drug delivery systems

1. RATE CONTROLLED
DRUG DELIVERY
SYSTEMS
Presented by:
AYESHA SAMREEN
I M.PHARM
DEPARTMENT OF PHARMACEUTICS
KLE COLLEGE OF PHARMACY, BANGALORE
1

2. • The term “SUSTAINED RELEASE” has been constantly used to
describe a pharmaceutical dosage form formulated to retard
the release of a therapeutic agent such that its appearance in
the systemic circulation is delayed and/or prolonged and its
plasma profile is sustained in the duration.
• The term “CONTROLLED RELEASE” is one which delivers the
drug at predetermined rate, for locally or systematically for a
specified period of time.
2

3. • CLASSIFICATION OF RATE CONTROLLED DRUG DELIVERY
SYSTEMS:
1 Rate-preprogrammed drug delivery systems
2 Activation-modulated drug delivery systems
3 Feedback-regulated drug delivery systems
4 Site-targeting drug delivery systems
3

4. Rate-preprogrammed drug
delivery systems
• In this group of controlled release drug delivery systems, the
release of the drug molecules from the delivery systems has
been preprogrammed at specific rate profiles. Fick’s law of
diffusion are often followed.
These systems can be further classified as follows:
a. Polymer membrane permeation- controlled drug delivery
systems.
b. Polymer matrix diffusion- controlled drug delivery systems.
c. Microreservoir partition-controlled drug delivery systems.
4

5. Polymer membrane permeation-
controlled drug delivery systems:
• In this type of
preprogrammed drug
delivery systems, a drug
formulation is totally or
partially encapsulated
within a drug reservoir
compartment.
• Different shapes and sizes
of drug delivery systems
can be fabricated.
5

6. • The rate of the drug release Q/t from this polymer membrane
permeation-controlled drug delivery system should be a constant
value and is defined by:
• Where, Km/r and Ka/m = partition coefficients for the interfacial
partitioning drug molecules from the reservoir to the rate
controlling membrane and from the membrane to the surrounding
aqueous diffusion layer.
• Dm and Dd = diffusion coefficients in the rate-controlling
membrane (with thickness hm) and in the aqueous diffusion layer
(with thickness hd).
• For a microporous or semipermeable membrane, the porosity
and tortuosity of the pores in the membrane should be included in
the determination of Dm and hm.
• CR is the drug concentration in the reservoir compartment.
6

7. • Representatives of this type of
drug delivery system are as
follows:
1 progestasert IUD: it is an
intrauterine device, the drug
reservoir is a suspension of
progesterone crystals in silicone
medical fluid and is encapsulated
in the vertical limb of a T-shaped
device walled by a non porous
membrane of ethylene-vinyl
acetate copolymer.
7

8. 2 Norplant subdermal
implant: it is fabricated from
nonporous silicone medical-
grade tubing(with both ends
sealed with silicone medical
grade adhesive)to
encapsulate either
levonorgestrel crystals alone
or a solid dispersion of
levonorgestrel in silicone
elastomer matrix. 8

9. 3 ocusert system: the drug
reservoir is a thin disk of
pilocarpine alginate
complex sandwiched
between two transparent
sheets of microporous
ethylene-vinyl acetate
copolymer membrane. 9

10. 4 Transderm-nitro is a transdermal therapeutic system in which
the drug reservoir, a dispersion of nitroglycerin-lactose triturate
in silicone medical fluid, is encapsulated in a thin ellipsoidal
patch.
10

11. Polymer matrix diffusion-
controlled drug delivery system:
• In this type of preprogrammed drug delivery system the drug
reservoir is prepared by homogenously dispersing drug
particles in a rate-controlling polymer matrix fabricated either
a lipophilic or hydrophilic polymer.
11

12. • Drug dispersion on the polymer matrix is accomplished by:
1. blending therapeutic dose of finely ground drug particles
with a drug polymer or a highly viscous base polymer,
followed by cross-linking of the polymer chains.
2. mixing the drug solids with a rubber polymer at an elevated
temperature.
12

13. • The resultant drug polymer dispersion is then molded or
extruded to form a drug delivery device of various shapes and
sizes.
• It can also be fabricated by dissolving the drug and the
polymer in a common solvent, followed by solvent
evaporation at an elevated temperature or under vacuum.
13

14. • The rate of drug release from this polymer matrix diffusion
controlled drug delivery system is time dependent and is
defined at steady state by :
Q/t½ = (2AC
R
D
p
) ½
A = initial drug loading dose in the polymer matrix.
C
R = drug solubility in the polymer.
D
p
= diffusivity of the drug molecules in the polymer matrix.
14

15. • Release of the drug molecules from this type of controlled
release drug delivery systems is controlled at a
preprogrammed rate by controlling the:
• Loading dose.
• Polymer solubility of the drug.
• Diffusivity in the polymer matrix.
15

16. • Representatives of this type of drug delivery system are as
follows:
 Nitro-dur: it is a transdermal drug delivery system.
 Fabricated by first heating an aqueous solution of water
soluble polymer, glycerol and PVA.
 The temperature of the solution is gradually lowered and
nitroglycerin and lactose triturate is dispersed just above the
congealing temperature of the solution.
16

17. • Mixture is then solidified in a mold at or below room
temperature and then sliced to form a medicated polymer
disk.
• After assembly on to a drug impermeable metallic plastic
laminate, a patch type TDD system is produced with an
adhesive rim surrounding the medicated disk.
• It is designed for application onto the intact skin for 24hrs.
• Used in case of angina pectoris.
17

18. • Compudose subdermal implant:
• It is fabricated by dispersing micronized estradiol crystals in a
viscos silicone elastomer and then coating the estradiol-
dispersing-polymer around a rigid (drug free) silicone rod by
extrusion to form a cylindrical implant.
18

19. • The rate of drug release from this reservoir gradient-
controlled drug delivery systems is defined as:
• ha (t) = thickness of the diffusional path through which the
drug molecules diffuse increased with time.
• (Cp(ha))= To compensate, the loading dose and/or the polymer
solubility of the impregnated drug.
19

20. Microreservoir partition-controlled
drug delivery systems
• In this type of preprogrammed drug delivery system the drug
reservoir is fabricated by microdispersion of an aqueous
suspension of drug using a high energy dispersion technique in
a biocompatible polymer, such as silicone elastomers, to form
a homogenous dispersion of many discrete ,unleachable,
microscopic drug reservoirs.
20

21. • Representatives of this type of drug delivery systems is as
follows:
1. Transdermal nitrodisc system:
• in the transdermal nitrodisc system the drug reservoir is
formed first preparing suspension of nitroglycerin and lactose
triturate in an aqueous solution of 40% polyethylene glycol
400.
• Dispersing the above mixture homogenously with isopropyl
palmitate ( dispersing agent) in a mixture of viscous silicone
elastomer.
21

22. • The resultant drug polymer dispersion is then molded to form
a solid medicated disk insitu on a drug-impermeable metallic
plastic laminate, with surrounding adhesive rim by injection
molding under instantaneous heating.
22

23. 2. Transdermal contraceptive device:
It is based on a patentable micro-drug-reservoir technique to
achieve a dual-controlled release of levonorgestrel, a potent
synthetic progestin, and estradiol, a natural estrogen at constant
and enhanced rates continuously for a period of 7 days.
23

24. • By applying 1 unit of transdermal contraceptive device per
week, beginning on day 5 of the individuals cycle for 3
consecutive weeks ( 3 weeks on and 1 week off), steady state
serum levels of levenorgestrel were obtained and
progesterone peak was effectively suppressed.
24

25. 3. Syncro-mate-C implant:
 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 elastomers by high-energy
dispersion.
25

26. ACTIVATION-MODULATED DRUG
DELIVERY SYSTEMS:
• In this group of controlled-release drug delivery systems the
release of drug molecules from the delivery systems is
activated by some physical, chemical or biochemical processes
and/or facilitated by the energy supplied externally.
26

27. Activation modulated drug delivery systems(DDS) can be classified into
the following categories:
1. Physical means
a. osmotic pressure activated DDS
b. hydrodynamic pressure activated DDS
c .vapor 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 27

28. Mechanically activated drug
delivery systems
• In this type of activation-controlled drug delivery system the
drug reservoir is a solution formulation retained in a
container equipped with mechanically activated pumping
system.
• The volume of solution delivered is controllable as small as
10-100µl.
• The volume of solution delivered is independent of the force
and duration of activation applied as well as the solution
volume in the container.
28

29. • Example is the development of the metered-dose nebulizer
• for the intranasal administration of a precision dose of
buserelin, which is a synthetic analog of luteinizing hormone
releasing hormone (LHRH) and insulin.
29

30. 30

31. Ph-Activated drug delivery
systems
• This type of DDS permits targeting the delivery of a drug only
in the region with a selected pH range.
• Intestinal pH activated DDS
• It is 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. such as the combination of ethyl cellulose and
HMC phthalate.
• The drug is release by drug dissolution and pore channel
diffusion mechanism.
31

32. 32

33. • In the stomach the coating membrane resists the action of
gastric fluid (ph < 3) and the drug ,molecules are thus
protected from acid degradation.
• After gastric emptying the drug delivery system travels to the
small intestine and the intestinal fluid activates the erosion of
the intestinal fluid-soluble HMC phthalate component from
the coating membrane.
• By adjusting the ratio of the intestinal fluid soluble polymer to
the intestinal fluid insoluble polymer, the membrane
permeability of a drug can be regulated as desired.
33

34. Osmotic activated drug
delivery system
• Osmosis can be defined as the net movement of water across
a selectively permeable membrane driven by a difference in
osmotic pressure across the membrane.
• It is driven by a difference in solute concentrations across the
membrane that allows passage of water, but rejects most
solute molecules or ions.
• Osmotic pressure created by osmogen is used as driving force
for these systems to release the drug in controlled manner.
34

35. • Osmotic pump offers many advantages over other controlled
drug delivery systems, that is,
 they are easy to formulate.
 simple in operation.
 improved patient compliance with reduced dosing frequency
and more consistence.
 prolonged therapeutic effect with uniform blood
concentration.
 inexpensive and their production scale up is easy.
35

36. • Osmotic drug-delivery systems suitable for oral administration
typically consist of a compressed tablet core that is coated
with a semipermeable membrane coating.
• This coating has one or more delivery ports through which a
solution or suspension of the drug is released over time.
• The core consists of a drug formulation that contains an
osmotic agent and a water swellable polymer.
36

37. • The rate at which the core absorbs water depends on the
osmotic pressure generated by the core components and the
permeability of the membrane coating.
• As the core absorbs water, it expands in volume, which
pushes the drug solution or suspension out of the tablet
through one or more delivery ports.
37

38. Materials used in formulation of
osmotic
system:1. semipermeable membrane
2. hydrophilic and hydrophobic polymers
3.wicking agents
4. solubilizing agents
5.osmogens
6.surfactants
7.coating solvents
8. plasticizers
9. pore forming agents
38

39. 1. Semipermeable
membrane:
• Cellulose acetate is a commonly employed semipermeable
polymer for the preparation of osmotic pumps.
• It is available in different acetyl content grades. Particularly,
acetyl content of 32% and 38% is widely used.
• Some of the polymers that can be used for above purpose
include cellulose esters such as cellulose acetate, cellulose
diacetate, cellulose triacetate, cellulose propionate, cellulose
acetate butyrate, and cellulose ethers like ethyl cellulose.
• Apart from cellulose derivatives, some other polymers such as
agar acetate, amylose triacetate, betaglucan acetate,
poly(vinyl methyl) ether copolymers, poly(orthoesters), poly
acetals and selectively permeable poly(glycolic acid),
poly(lactic acid) derivatives, and Eudragits can be used as
semipermeable film-forming materials 39

40. 2. Hydrophilic and hydrophobic
polymers:
• These polymers are used in the formulation development of
osmotic systems for making drug containing matrix core.
• The highly water soluble compounds can be coentrapped in
hydrophobic matrices and moderately water soluble
compounds can be coentrapped in hydrophilic matrices to
obtain more controlled release.
• The polymers are of either swellable or nonswellable nature.
Mostly, swellable polymers are used for the pumps containing
moderately water-soluble drugs.
40

41. • Ionic hydrogels such as sodium carboxymethyl cellulose are
preferably used because of their osmogenic nature.
• Hydrophilic polymers such as hydroxy ethyl cellulose, carboxy
methylcellulose, hydroxy propyl methylcellulose, high-
molecular-weight poly(vinyl pyrrolidone), and
• hydrophobic polymers such as ethyl cellulose and wax
materials can be used for this purpose.
41

42. 3. Wicking agents:
•
A wicking agent is defined as a material with the ability to
draw water into the porous network of a delivery device.
• The wicking agents are those agents which help to increase
the contact surface area of the drug with the incoming
aqueous fluid.
• The use of the wicking agent helps to enhance the rate of drug
released from the orifice of the drug.
• A wicking agent is of either swellable or nonswellable nature .
• They are characterized by having the ability to undergo
physisorption with water.
42

43. • Physisorption is a form of absorption in which the solvent
molecules can loosely adhere to surfaces of the wicking agent
via Van der Waals interactions between the surface of the
wicking agent and the adsorbed molecule.
• The function of the wicking agent is to carry water to surfaces
inside the core of the tablet, thereby creating channels or a
network of increased surface area .
• The examples are colloidal silicon dioxide, PVP and Sodium
lauryl sulfate.
43

44. 4. Solubilizing Agents
• For osmotic drug delivery system, highly water-soluble drugs
would demonstrate a high release rate that would be of zero
order.
• Thus, many drugs with low intrinsic water solubility are poor
candidates for osmotic delivery. However, it is possible to
modulate the solubility of drugs within the core.
• Addition of solubilizing agents into the core tablet dramatically
increases the drug solubility.
44

45. • Nonswellable solubilizing agents are classified into three groups,
1. Agents that inhibit crystal formation of the drugs or otherwise act
by complexation with the drugs (e.g., PVP, poly(ethylene glycol)
(PEG 8000) and β-cyclodextrin),
2. a micelle-forming surfactant with high HLB value, particularly
nonionic surfactants (e.g., Tween 20, 60, and 80, polyoxyethylene
or poly ethylene containing surfactants and other long-chain
anionic surfactants such as SLS),
45

46. 3. citrate esters (e.g., alkyl esters particularly triethyl citrate)
and their combinations with anionic surfactants. The
combinations of complexing agents such as polyvinyl
pyrrolidone (PVP) and poly(ethylene glycol) with anionic
surfactants such as SLS are mostly preferred.
46

47. 5. Osmogens
• Upon penetration of biological fluid into the osmotic pump
through semipermeable membrane, osmogens are dissolved
in the biological fluid, which creates osmotic pressure buildup
inside the pump and pushes medicament outside the pump
through delivery orifice.
• They include inorganic salts and carbohydrates.
• Mostly, potassium chloride, sodium chloride, and mannitol
used as osmogens.
• Generally combinations of osmogens are used to achieve
optimum osmotic pressure inside the system
47

48. 6. Surfactants
•
Surfactants are particularly useful when added to wall-forming
material.
• The surfactants act by regulating the surface energy of
materials to improve their blending into the composite and
maintain their integrity in the environment of use during the
drug release period.
• Typical surfactants such as poly oxyethylenated glyceryl
recinoleate, polyoxyethylenated castor oil having ethylene
oxide, glyceryl laurates, and glycerol (sorbiton oleate, stearate,
or laurate) are incorporated into the formulation.
48

49. 7. Coating Solvents
•
Solvents suitable for making polymeric solution that is used
for manufacturing the wall of the osmotic device include inert
inorganic and organic solvents that do not adversely harm the
core and other materials.
• The typical solvents include methylene chloride, acetone,
methanol, ethanol, isopropyl alcohol, butyl alcohol, ethyl
acetate, cyclohexane, carbon tetrachloride, and water.
49

50. 8. Plasticizers
• plasticizers, or low molecular weight diluents are added to
modify the physical properties and improve film-forming
characteristics of polymers.
• Plasticizers can change visco elastic behavior of polymers
significantly .
• Plasticizers can turn a hard and brittle polymer into a softer,
more pliable material, and possibly make it more resistant to
mechanical stress .
50

51. • PEG-600, PEG-200, triacetin (TA), dibutyl sebacate, ethylene
glycol monoacetate, ethylene glycol diacetate, triethyl
phosphate, and diethyl tartrate used as plasticizer in
formulation of semipermeable membrane .
51

52. 9. Pore-Forming Agents
•
These agents are particularly used in the pumps developed for
poorly water-soluble drugs and in the development of
controlled porosity or multiparticulate osmotic pumps .
• These pore-forming agents cause the formation of
microporous membrane.
• The pore-formers can be inorganic or organic and solid or
liquid in nature.
52

53. For example, alkaline metal salts such as sodium chloride,
sodium bromide, potassium chloride, potassium sulphate,
potassium phosphate, and so forth,
 alkaline earth metals such as calcium chloride and calcium
nitrate, carbohydrates such as sucrose, glucose, fructose,
mannose, lactose, sorbitol, and mannitol, and
 diols and polyols such as poly hydric alcohols, polyethylene
glycols, and polyvinyl pyrrolidone can be used as pore-forming
agents .
53

54. • Triethyl citrate (TEC) and triacetin (TA) are also used to create
pore in the membrane. Membrane permeability to the drug is
further increased addition of HPMC or sucrose .
54

55. Creation of Delivery Orifice
• Osmotic delivery systems contain at least one delivery orifice
in the membrane for drug release.
• On the other hand, size of delivery orifice should not also be
too large, otherwise, solute diffusion from the orifice may take
place.
55

56. • Optimum orifice diameter is in the range of 0.075–0.274 mm.
At orifice size of 0.368 mm and above, control over the
delivery rate is lost .
• If the size of delivery orifice is too small, zero-order delivery
will be affected because of development of hydrostatic
pressure within the core.
56

57. • Delivery orifices in the osmotic systems can be created with
the help of a mechanical drill .
• Laser drilling is one of the most commonly used techniques to
create delivery orifice in the osmotic tablet.
• Laser beam is fired onto the surface of the tablet that absorbs
the energy of the beam and gets heated ultimately causing
piercing of the wall and, thus forming orifice.
57

58. • It is possible to control the size of the passageway by varying
the laser power, firing duration (pulse time), thickness of the
wall, and the dimensions of the beam at the wall.
58

59. • In some of the oral osmotic systems, there is in situ formation
of delivery orifice .
• The system described consists of a incorporation of pore-
forming agents into the coating solution.
• Pore-forming agents are water soluble: upon contact with the
aqueous environment, they dissolve in it and leach out from
membrane, creating orifice.
59

60. Types of Osmotic Pumps
1. Rose-Nelson Pump
2. Higuchi-Leeper Osmotic Pump
3. Higuchi-Theeuwes Osmotic Pump
4. Elementary Osmotic Pump (EOP)
5. Push-Pull Osmotic Pump (PPOP)
6. Controlled Porosity Osmotic Pump (CPOP)
7. Liquid-Oral Osmotic (L-OROS) System
8. Sandwiched Osmotic Tablet (SOT)
60

61. 1. Rose-Nelson Pump
• Rose and Nelson, the
Australian scientists, were
initiators of osmotic drug
delivery. In 1955, they
developed an implantable
pump for the delivery of
drugs to the sheep and cattle
gut.
• The Rose-Nelson implantable
pump is composed of three
chambers: a drug chamber, a
salt chamber holding solid
salt, and a water chamber.
• A semipermeable membrane
separates the salt from water
chamber.
61

62. • The movement of water from the water chamber towards salt
chamber is influenced by difference in osmotic pressure
across the membrane.
• Conceivably, volume of salt chamber increases due to water
flow, which distends the latex diaphragm dividing the salt and
drug chambers: eventually, the drug is pumped out of the
device.
62

63. • The major problem associated with
• Rose-Nelson pumps was that the osmotic action began
whenever water came in contact with the semipermeable
membrane. This needed pumps to be stored empty and water
to be loaded prior to use.
63

64. Higuchi-Leeper pump
• The Higuchi-Leeper pump has no water chamber, and the
activation of the device occurs after imbibition of the water
from the surrounding environment.
• Higuchi-Leeper pumps contain a rigid housing and a semi
permeable membrane supported on a perforated frame; a salt
chamber containing a fluid solution with an excess of solid
salt.
64

65. • Upon administration/implantation, surrounding biological
fluid penetrates into the device through porous and
semipermeable membrane and dissolves the MgSO4, creating
osmotic pressure inside the device that pushes movable
separator toward the drug chamber to remove drug outside
the device.
• It is widely employed for veterinary use.
65

66. • The Pulsatile release of
drug is achieved by
drilling the orifice in
elastic material that
stretches under the
osmotic pressure.
• Pulse release of drug is
obtained after
attaining a certain
critical pressure, which
causes the orifice to
open. 66

67. • The pressure then reduces to cause orifice closing and the
cycle repeats to provide drug delivery in a pulsatile fashion.
• The orifice should be small enough to be substantially closed
when the threshold level of osmotic pressure is not present
67

68. Higuchi-Theeuwes Osmotic
Pump
• In this device, the rigid
housing consisted of a
semipermeable
membrane.
• This membrane is
strong enough to
withstand the pumping
pressure developed
inside the device due
to imbibition of water.
68

69. • The drug is loaded in the device only prior to its application,
which extends advantage for storage of the device for longer
duration.
• The release of the drug from the device is governed by the salt
used in the salt chamber and the permeability characteristics
of the outer membrane.
69

70. • Small osmotic pumps of
this form are available
under trade name Alzet
made by Alza
Corporation in 1976.
• They are used frequently
as implantable
controlled release
delivery systems in
experimental studies
requiring continuous
administration of drugs.
70

71. Elementary Osmotic Pump
(EOP)
• Elementary osmotic pump was
invented by Theeuwes in 1974 .
• it essentially contains an active
agent having a suitable osmotic
pressure; it is fabricated as a
tablet coated with semi
permeable membrane, usually
cellulose acetate .
• A small orifice is drilled through
the membrane coating.
•
71

72. • When this coated tablet is exposed to an aqueous
environment, the osmotic pressure of the soluble drug inside
the tablet draws water through the semi permeable coating
and a saturated aqueous solution of drug is formed inside the
device.
• The membrane is nonextensible and the increase in volume
due to imbibition of water raises the hydrostatic pressure
inside the tablet, eventually leading to flow of saturated
solution of active agent out of the device through a small
orifice.
72

73. Push-Pull Osmotic Pump
(PPOP)
• Push-pull osmotic pump is
delivered both poorly
water soluble and highly
water soluble drugs at a
constant rate.
• This system resembles a
standard bilayer coated
tablet. One layer (the
upper layer) contains drug
in a formulation of
polymeric osmotic agent,
and other tablet excipients.
• This polymeric osmotic
agent has the ability to
form a suspension of drug
in situ. 73

74. • When this tablet later imbibes water, the other layer contains
osmotic and colouring agents, polymer and tablet excipients.
• These layers are formed and bonded together by tablet
compression to form a single bilayer core.
• The tablet core is then coated with semipermeable
membrane.
• After the coating has been applied, a small hole is drilled
through the membrane by a laser or mechanical drill on the
drug layer side of the tablet.
74

75. • When the system is placed in aqueous environment, water is
attracted into the tablet by an osmotic agent in both the
layers.
• The osmotic attraction in the drug layer pulls water into the
compartment to form in situ a suspension of drug.
• The osmotic agent in the nondrug layer simultaneously
attracts water into that compartment, causing it to expand
volumetrically, and the expansion of nondrug layer pushes the
drug suspension out of the delivery orifice .
75

76. Controlled Porosity Osmotic
Pump (CPOP)
• Controlled porosity osmotic
pump (CPOP) are reliable
drug delivery system and
could be employed as oral
drug delivery system.
• CPOP consists of drug and
osmogen in the core and
tablet is surrounded by a
semipermeable membrane
containing leachable pore
forming agents which in
contact with aqueous
environment dissolves and
result in formation of micro
porous membrane.
• 76

77. • The membrane after formation of pores became permeable
for both water and solutes.
• Drug release from these systems is independent of pH and
other physiological parameters.
• Zero order release characteristics could be achieved by
optimizing the parameters of the delivery system
77

78. • Drug release rate from CPOP depends on various factors like
• coating thickness,
• solubility of drug in tablet core,
• level of leachable pore-forming agent(s) and
• the osmotic pressure difference across the membrane .
78

79. • Advantages:
The stomach irritation problems are considerably reduced, as
drug is released from the whole of the device surface rather
from a single hole .
Further, no complicated laser-drilling unit is required because
the holes are formed in situ.
79

80. Liquid-Oral Osmotic (L-OROS)
System
• Each of these systems
includes a liquid drug
layer, an osmotic engine
or push layer, and a
semipermeable
membrane coating.
• When the system is in
contact with the
aqueous environment,
water permeates across
the rate-controlling
membrane and activates
the osmotic layer. 80

81. Sandwiched Osmotic Tablet
(SOT)
• sandwiched osmotic tablet is composed of polymeric push
layer sandwiched between two drug layers with two delivery
orifices.
81

82. • When placed in the
aqueous environment,
the middle push layer
containing the swelling
agents' swells and the
drug is released from the
two orifices situated on
opposite sides of the
tablet; thus sandwiched
osmotic tablets (SOTS)
can be suitable for drugs
prone to cause local
irritation of the gastric
mucosa.
82

83. Product name Active pharmaceutical ingredient Design of osmotic pump
Acutrim Phenylpropanolamine Elementary pump osmotic pump [9]
Alpress LP Prazosin Push-pull osmotic pump [2]
Cardura XL Doxazosin Push-pull osmotic pump [34]
ChronogesicTM Sufentanil Implantable osmotic system [8]
Covera HS Verapamil Push-pull osmotic pump with time delay [48]
Ditropan XL Oxybutinin chloride Push-pull osmotic pump [9]
Dynacirc CR Isradipine Push-pull osmotic pump [34]
Efidac 24 Pseudoephiderine Elementary pump osmotic pump [8]
Efidac 24 Chlorpheniramine meleate Elementary pump osmotic pump
Glucotrol XL Glipizide Push-pull osmotic pump [11]
Invega Paliperidone Push-pull osmotic pump [8]
Minipress XL Prazocine Elementary osmotic pump [19]
Procadia XL Nifedipine Push-pull osmotic pump [48]
Sudafed 24 Pseudoephedrine Elementary osmotic pump [19]
Viadur Leuprolide acetate Implantable osmotic system [9]
Volmex Albuterol Elementary osmotic pump [12]
83

84. 84

85. Enzyme activated drug delivery
systems
• This type of activation modulated DDS depends on the
enzymatic process to activate the release of the drug.
• In this system the drug reservoir is either physically entrapped
in microspheres or chemically bound to the polymer chains
from biopolymers, such as albumins or polypeptides.
85

86. • The release of drug is activated by the enzymatic hydrolysis of
biopolymers by a specific enzyme in the target tissue.
• Typical example of this enzyme activated DDS is the
development of albumin microspheres that release 5-
fluorouracil in a controlled manner by protease activated
biodegradation.
86

87. Feedback regulated drug delivery
system
• In this group of controlled-release DDS the release of drug
molecules from the delivery systems is activated by triggering
agent, such as a biochemical substance, in the body.
• The rate of drug release is then controlled by the
concentration of triggering agent detected by a sensor in the
feedback-regulated mechanisms.
87

88. • It is classified in to the following:
1) Bioerosion-regulated drug delivery systems
2) Bioresponsive drug delivery systems
3) Self regulating drug delivery systems
88

89. 1. Bioerosion-regulated drug
delivery systems
• The feedback-regulated DDS was applied to the development
of a bioerosion-regulated DDS by heller and trescony.
• the system consisted of drug dispersed bioerodible matrix
fabricated from poly(vinyl methyl ether) half-ester , which was
coated with a half layer of immobilized urease.
• In a solution of neutral pH, the polymer only erodes slowly.
89

90. • In the presence of
urea, urease at the
surface of DDS
metabolizes urea to
form ammonia.
• This causes the pH to
increase and a rapid
degradation of
polymer matrix as
well as the release of
drug molecules. 90

91. Bioresponsive drug delivery
system
• Bioresponsive DDS was developed by Horbett et al.
• Drug reservoir is contained in a device enclosed by a
bioresponsve polymeric membrane whose drug permeability
is controlled by the concentration of a biochemical agent in
the tissue where the system is located.
91

92. • Typical example of this
bioresponsive DDS is the
development of a
glucose-triggered insulin
delivery system in which
the insulin reservoir is
encapsulated within a
hydrogel membrane
having pendent NR2
groups.
• In alkaline solution the –
NR2 groups are neutral
and the membrane is
unswollen and
impermeable to insulin. 92

93. • Glucose is a
triggering agent,
penetrates in to the
membrane , it is
oxidized
enzymatically by the
glucose oxidase
entrapped in the
membrane to form
gluconic acid. 93

94. • The –NR2 groups are protonated to form –NR2H and the
hydrogel membrane then becomes swollen and permeable to
insulin molecules.
94

95. Self-regulating drug delivery
systems
• This type of feedback-regulated drug delivery system depends
on a reversible and competitive binding mechanism to
activate and regulate the release of the drug.
• In this system the drug reservoir is drug complex
encapsulated within a semipermeable membrane polymeric
membrane.
• The release of drug is activated by the polymeric membrane
of a biochemical agent from the tissue in which the system is
located.
95

96. • Kim et al. first applied the mechanism of reversible binding of
sugar molecules by lectin into the design of self-regulating
DDS.
96

97. • It first involves the reparation of biologically active insulin
derivatives in which insulin is coupled with a sugar (maltose)
and this into an insulin-sugar-lectin complex.
• Complex is then encapsulated within a semipermeable
membrane.
• As blood glucose diffuses into the device and competitively
binds at the sugar binding sites in lectin molecules.
• This activates the release of bound insulin-sugar derivatives.
97

98. • Complex of glycosylated insulin-concanavalin A, which is
encapsulated inside a polymer membrane.
• As glucose, the triggering agent, penetrates the system, it
activates the release of glycosylated insulin from the complex
for controlled delivery out of the system.
98

99. • References:
1. Novel drug delivery systems by Yie W. Chein. Pg no 1 – 37
2. Osmotic drug delivery systems
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407637/
3. Images from Google
99

100. Thank you
100