RATE CONTROLLED DRUG
DELIVERY SYSTEM
Presented by,
M. Gayathri
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CONTENTS
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1. INTRODUCTION
2. SUSTAINED RELEASE Vs CONTROLLED RELEASE
3. ADVANTAGES & DISADVANTAGES
4. TYPES
I. RATE-PREPROGRAMMED DDS
A. POLYMER MEMBRANE PERMEATION CONTROLLED DDS
B. POLYMER MATRIX- DIFFUSION CONTROLLED DDS
C. MICRORESERVOIR- PARTITION CONTROLLED DDS
II. ACTIVATION- MODULATED DDS
A. PHYSICAL MEANS
B. CHEMICAL MEANS
C. BIOCHEMICAL MEANS
III. FEEDBACK REGULATED DDS
A. BIOEROSION- REGULATED DDS
B. BIORESPONSIVE DDS
C. SELF-REGULATING DDS
IV. SITE SPECIFIC DDS
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5. REFERENCE
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INTRODUCTION
▪ Conventional drug delivery systems are the primary pharmaceutical products
commonly seen in the prescription and OTC drug market place, which are
known to provide a prompt release of drug.
▪ Therefore to achieve as well as to maintain the drug concentration within
the therapeutically effective range needed for treatment, it is often necessary to
take this type of medication or drug delivery systems viz., tablets, capsules,
pills, suppositories, creams, ointments, liquids, aerosols and injectables as drug
carriers. This results in a significant fluctuations in drug levels.
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▪ Recently, several technical advancements have been made. They have
resulted in the development of new techniques for drug delivery. These
techniques are capable of controlling the,
❑ Rate of drug delivery
❑ Sustaining the duration of therapeutic action
❑ Targeting the delivery of drug to a specific tissue.
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SUSTAINED RELEASE Vs CONTROLLED RELEASE
SUSTAINED RELEASE: CONTROLLED RELEASE:
This term constantly used to It implies a predictability and
describe a pharmaceutical reproducibility in the drug
dosage form formulated to release kinetics, which means
retard the release of a that the release of drug at a rate
therapeutically active agent profile that is not only
such that its appearance in the predictable kinetically, but also
systemic circulation is delayed reproducible from one unit to
and/or prolonged and its plasma another.
profile is sustained in duration
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SUSTAINED RELEASE CONTROLLED RELEASE
In this initial dose of drug is Which delivers drug at a
released immediately and predetermined rate for a
remaining maintenance dose specified period of time.
is released slowly to achieve
prolonged therapeutic level
which is not constant.
Constitutes a dosage form that Constitutes dosage form that
provides medication over maintains constant drug levels
extended period of time. in blood or tissues.
SRDF generally do not attain Maintains constant drug levels
zero order release kinetics. in the blood target tissue
usually by releasing the drug in
a zero order pattern, i.e., the
drug release over time
irrespective of concentration.
Usually do not contain It contain methods to promote
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localization of the drug wawwt.DusloiMteix..com
active site.
ADVANTAGES
✓ Reduced frequency of dosing.
✓ Dose reduction.
✓ Improved patient compliance.
✓ Reduced toxicity due to overdose.
✓ Reduces the fluctuations in peak plasma concentration.
✓ Night time dosing can be avoided.
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DISADVANTAGES
✓ Decreased systemic availability in comparison to immediate release
conventional dosage form.
✓ Poor in vivo-in vitro correlation.
✓ Possibility of dose dumping.
✓ Retrieval of drug is difficult.
✓ Higher cost of formulation.
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TYPES OF RATE-CONTROLLED
DRUG DELIVERY SYSTEMS
RATE- ACTIVATION-
PREPROGRAMMED MODULATED DRUG
DRUG DELIVERY DELIVER SYSTEMS
SYSTEMS
FEEDBACK- REGULATED SITE-TARGETING
DRUG DELIVERY DRUG DELIVERY
SYSTEMS SYSTEMS
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I. RATE- PREPROGRAMMED DRUG
DELIVERY SYSTEMS
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▪ In this system, the release of drug molecules from the delivery systems has been pre-
programmed at specific rate profiles.
▪ This was 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.
▪ Fick’s law of diffusion are often followed.
▪ These systems can be further classified as,
1. Polymer membrane – permeation controlled systems
2. Polymer matrix – diffusion controlled systems
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1. POLYMER MEMBRANE- PERMEATION CONTROLLED SYSTEMS
▪ A drug formulation is totally or partially encapsulated within a drug reservoir compartment.
▪ The drug release surface is covered by a RATE-CONTROLLING POLYMERIC
MEMBRANE having a specific permeability.
▪ The drug reservoir may exist in solid, solution or suspension form.
▪ The polymeric membrane can be fabricated from nonporous(homogenous or heterogeneous)
OR a micro porous (semipermeable) polymeric material.
▪ ENCAPSULATION of drug formulation inside the reservoir compartment is done by,
✓ INJECTION MOLDING
✓ SPRAY COATING
✓ CAPSULATION
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✓ MICROENCAPSULATION
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Various shapes of polymer membrane permeation controlled drug delivery systems.
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▪ The rate of drug release (Q/t) should be a constant for this system and it can be defined by,
𝐾𝑚
𝑄 Τ𝐾𝑎 𝐷
𝑟 Τ𝑚𝐷𝑑 𝑚
𝐶
= 𝑅
𝑡 𝐾𝑚Τ 𝐷𝑚ℎ𝑑+ 𝐾𝑎Τ 𝐷 ℎ
𝑟 𝑚 𝑑 𝑚
Where, 𝐾𝑚Τ𝑟 → Partition co-efficient of drug from reservoir to rate controlling membrane
𝐾𝑎Τ𝑚 → Partition coefficient of drug from rate controlling membrane
to surrounding aqueous diffusion layer
𝐷𝑚 → Diffusion co-efficient in rate controlling membrane having thickness ℎ𝑚
𝐷𝑑 → Diffusion co-efficient in aqueous diffusion layer
having thickness ℎ 𝑑
𝐶𝑅 → Concentration of drug in reservoir compartment
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▪ The rate of drug release is programmed by controlling the,
1. Partition coefficient
2. Diffusivity of drug molecule
3. Thickness of rate-controlling membrane
EXAMPLE: PROGESTASERT INTRA UTERINE DEVICE (IUD)
▪ Drug reservoir is a suspension of progesterone crystals in silicone medical fluid and
is encapsulated in the vertical limb of T-shaped device walled by a non-porous
membrane of Ethylene vinyl acetate co-polymer.
▪ Release rate- 65 mcg/day for 1 year, in the uterine cavity to achieve contraception.
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2. POLYMER MATRIX- DIFFUSION CONTROLLED DRUG DELIVERY
SYSTEMS
▪ Drug reservoir is prepared by homogenously dispersing drug particles in a rate
controlling polymer matrix fabricated from either a lipophilic or hydrophilic
polymer.
▪ Drug dispersion in polymer matrix is accomplished by,
➢ Blending a therapeutic dose of finely ground drug particles with a
liquid polymer or a highly viscous base polymer, followed by cross-
linking of polymer chains.
➢ Mixing drug solids with a rubbery polymer at an elevated temperature
and is molded to form DDS.
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▪ The rate of drug release is time dependent for this system and is defined at a steady state by,
𝑄 1
= (2ACRDP) ൗ2
1
𝑡 ൗ2
Where,
A = initial drug loading dose in polymer matrix.
CR=drug solubility in polymer (drug reservoir conc. in system)
DP = diffusivity of drug molecules in polymer matrix.
▪ The release of drug is controlled at a preprogrammed rate by controlling the
loading dose, polymer solubility of drug and diffusivity of drug in polymer
matrix.
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EG: NITRO-DUR, A TRANSDERMAL DDS
▪ It is fabricated by first heating an aqueous solution of water soluble polymer, glycerol
and polyvinyl alcohol.
▪ The temperature of solution is then gradually lowered and nitroglycerine and lactose
triturate are dispersed just above the congealing temperature of solution.
▪ The mixture is then solidified in mold at or below room temperature and then sliced to
form a medicated polymer disk.
▪ Dosage rate: 0.5 mcg / cm2 / day onto a intact skin.
▪ Use: For the treatment of angina pectoris to provide a continuous transdermal infusion of
nitroglycerine
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Occlusive
Impermeable
base plate
Adsorbent pad backing (polythene
(aluminium
cover slip)
foil)
Adhesive rim
(micro porous
acrylic polymer
rim) DRUG RELEASE
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3. MICRORESERVOIR PARTITION- CONTROLLED DRUG DELIVERY
SYSTEMS.
▪ In this type drug reservoir is fabricated by micro dispersion 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 microscopic drug
reservoirs.
▪ Different shapes and sizes of drug delivery system devices can be fabricated from this
micro reservoir DDS by molding or extrusion.
▪ Depending on physicochemical properties of drug and the desired rate of drug release
rate, the device can be further coated with a layer of biocompatible polymer to modify the
mechanism and release rate.
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▪ The rate of drug release (dQ / dt) is defined by,
𝑑𝑄 𝐷𝑝𝐷𝑑𝑚𝐾 𝑆 −𝑛) 1 1
= 𝑝 𝐷
nS – 𝑙 𝑙(1 +
𝑑𝑡 𝐷𝑝ℎ𝑑+𝐷𝑑ℎ𝑝𝑚𝐾𝑝 p ℎ 𝐾𝑙 𝐾𝑚
𝑙
Where, m= a/b
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a = ratio of drug conc in bulk of elution solution over drug solubility in the same medium.
b = ratio of drug conc at the outer edge of the polymer coating membrane over the drug
solubility in same polymer.
n = ratio of drug conc at the inner edge of interfacial barrier over the drug solubility in the
polymer matrix
Km = partition coefficient for interfacial partitioning of drug from polymer matrix to
polymer coating membrane.
K partition coefficient for interfacial partitioning of drug from liquid
l =
compartments to polymer matrix.
K partition coefficient for interfacial partitioning of drug from
p =
polymer coating membrane to elution solution.
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Dl = diffusivity of drug in liquid layer surrounding the drug particles.
DP = diffusivity of drug in polymer coating membrane enveloping polymer matrix.
Dd = diffusivity of drug in hydrodynamic diffusion layer surrounding the polymer coating
membrane.
hl, hp, hd = thickness.
Sl = solubility of drug in liquid compartments.
Sp = solubility of drug in polymer matrix.
▪ Release of drug molecules from this type of CDDS can follow either dissolution or matrix
diffusion-controlled process depending on relative magnitude of Sl and Sp.MyPharmaGuide.Com 26
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EXAMPLE: TRANSDERMAL NITRO DISC SYSTEM
▪ The drug reservoir is formed by first preparing a suspension of nitroglycerine and
lactose triturate in an aqueous solution of 40% PEG 400 and dispersing it
homogenously with isopropyl palmitate, as dispersing agent, in a mixture of
viscous silicone elastomers by high energy mixing and then cross linking the
polymer chain by catalyst.
▪ It is then molded to form a solid medicated disk, on a drug-impermeable metallic
plastic laminate with surrounding adhesive rim, by injection molding under
instantaneous heating.
▪ Release rate: 0.5 mg / cm2 / day , to treat ANGINA PECTORIS.
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CROSS – SECTIONAL VIEW OF NITRODISC.
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II. ACTIVATION MODULATED DRUG DELIVERY
SYSTEMS
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▪ In this system, the release of drug molecules from the delivery system is activated by some,
1. Physical means.
2. Chemical means.
3. Biological process.
4. External energy.
▪ The rate of drug release is then controlled by regulating the process applied or energy input.
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CLASSIFICATION (BASED ON NATURE OF PROCESS APPLIED OR TYPE OF
ENERGY USED)
1. PHYSICAL MEANS A. Osmotic pressure activated DDS
B. Hydrodynamic pressure activated DDS
C. Vapour 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 A. pH activated DDS
MEANS B. Ion activated DDS
C. Hydrolysis activated DDS
3. BIOCHEMICAL A. Enzyme activated DDS
MEANS
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PHYSICAL MEANS
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A. OSMOTIC PRESSURE ACTIVATED DDS
▪ Osmotic drug delivery uses the osmotic pressure for controlled delivery of drugs by
using osmogens.
▪ These system can be used for both route of administration i.e.., oral and parenteral.
▪ Osmogens: sodium chloride, potassium chloride.
▪ In this system, drug reservoir can be solution or a solid formulation and is contained
within a semi permeable housing with controlled water permeability.
▪ The drug is activated to release in a solution form, at a constant rate through a
special delivery orifice with Pore size: 0.4 µm.
▪ The rate of drug release is modulated by controlling osmotic pressure gradient.
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▪ The intrinsic rate of drug release Q / t is defined by,
𝑄 𝑃
For a solution formulation, = 𝑤 (𝜋 − 𝜋
𝑡 ℎ 𝑠 𝑒)
𝑚
𝑄 𝑃
For a solid formulation, = 𝑤 𝜋 𝜋 S
ℎ 𝑠 −𝑡 𝑒 d
𝑚
Where,
Pw → Water permeability
Am → Effective surface area
hm → Thickness of semipermeable housing
Sd → Aqueous solubility of solid drug
𝞹s → Osmotic pressure of drug delivery system
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e → Osmotic pressure of environment
CLASSIFICATION OF OSMOTIC DDS
IMPLANTABLE OSMOTIC DDS ORAL OSMOTIC DDS
1. Rose nelson pump. 1. Elementary osmotic pump
2. Higuchi leeper osmotic pump. 2. Modified osmotic pump
3. Higuchi theeuwes osmotic pump. 3. Multi chamber osmotic pump
4. Alzet osmotic pump. 4. Controlled porosity osmotic pump
5. Multi particulate delayed release system
6. Monolithic osmotic system
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EG: ALZET OSMOTIC PUMP
• In Alzet osmotic pump, the drug reservoir which is normally a solution formulation
is contained within collapsible, impermeable polyester bags.
• The external surface of reservoir is coated with a layer of osmotically active salt,
such as sodium chloride .
• This reservoir compartment is then completely sealed inside a rigid housing walled
with a semipermeable membrane at the implantation site.
• The water component in the tissue fluid penetrates through the semipermeable
housing to dissolve osmotically active salt .
• This creates an osmotic pressure in the narrow spacing between the flexible reservoir
compartment wall and rigid semipermeable housing.
• Under the osmotic pressure the reservoir compartment is forced to reduce its volume and
drug solution is delivered at a controlled rate.
• The drug concentration in the solution, different doses of drug can be delivered at a
constant rate for a period of 1-4 weeks.
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B. HYDRODYNAMIC PRESSURE ACTIVATED DDS
▪ This system is fabricated by enclosing a collapsible, impermeable container,
which contains a liquid drug formulation to form a drug reservoir, inside a rigid
shape retaining housing.
▪ A composite laminate of an absorbent layer and a swellable, hydrophilic
polymer layer (poly hydroxy alkyl methacrylate) is sandwiched between drug
reservoir and the housing.
▪ In GIT, the laminate absorbs GI fluid through annular opening at the lower
end of the housing and swells generating hydrodynamic pressure which forces
the drug reservoir compartment to reduce in volume and causes the liquid drug
formulation to release through the delivery orifice.
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HYDRODYNAMIC PRESSURE ACTIVATED DDS –A CROSS SECTIONAL VIEW
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▪ The rate of drug delivery through the delivery orifice can be defined as,
𝑄 𝑃 𝐴
= 𝑓 𝑚 (𝞠 – 𝞠
𝑡 ℎ s e)
𝑚
Where,
Pf → Fluid permeability
Am → Effective surface area
hm → Thickness of the wall with annular openings
(𝞠s – 𝞠e) → Difference in hydrodynamic pressure of system(𝞠s) and
environment(𝞠e)
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C. VAPOUR PRESSURE ACTIVATED DDS
▪ In this type of system the drug reservoir(which also exist as a solution
formulation) is contained inside the infusion compartment.
▪ It is physically separated from pumping compartment by freely movable partition.
▪ The pumping compartment contains a fluorocarbon fluid that vaporizes at body
temperature at the implantation site and creates a vapor pressure.
▪ Under the vapor pressure created the partition moves upward.
▪ This forces the drug solution in the infusion compartment to be delivered through
a series of flow regulator and delivery cannula into blood circulation at a
constant flow rate.
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▪ The rate of drug delivery Q / t is defined by,
𝑄 𝑑4(𝑃𝑠−𝑃𝑒)
=
𝑡 40.74𝜇𝑙
Where,
d → Inner diameter of delivery cannula.
l → Inner length of delivery cannula.
Ps-Pe → Difference between vapour pressures at pumping compartment
and implantation site.
𝞵→ Viscosity of the formulation used.
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▪ Release of drug is activated by vapor pressure and controlled at a rate
determined by differential vapor pressure, formulation viscosity and size of
delivery cannula.
EG: INFUSAID
▪ Development of implantable infusion pump (infusaid) for constant
infusion of,
1. HEPARIN – in anticoagulation treatment
2. INSULIN – in anti-diabetic medication
3. MORPHINE – in patients with intense pain of terminal cancer
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1- flow regulator,
2-silicone polymer coating,
3-partition,
4-pumping compartment,
5-infusate compartment,
6-fluorocarbon fluid filling tube,
7-filter assembly,
8-inlet septum for percutaneous refill of
infusate,
9-needle stop
A VAPOUR PRESSURE –ACTIVATED DDS, CROSS SECTIONAL VIEW OF INFUSAID.
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D. MECHANICALLY ACTIVATED DRUG DELIVERY SYSTEMS4
▪ In this type of activation controlled drug delivery system, the drug reservoir
is a solution formulation retained in a container equipped with a
mechanically activated pumping system.
▪ A measured dose of drug formulation is reproducibly delivered into a body
cavity.
▪ The volume of solution delivered is controllable as a small as 10-100µl, and
is independent of,
➢ The force and duration of activation applied
➢ The solution volume in the container.
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EG: METERED DOSE INHALER
▪ For the intranasal administration of a precision dose of,
• LHRH- Leutinizing Hormone Releasing Hormone(BUSERELIN)
• Bronchodilators – Salbutamol
• Corticosteroids – Beclomethasone
• Immune modulators – Cyclosporine
▪ Advantage – Avoidance of first pass metabolism
PUMPING SYSTEM OF
METERED DOSE
INHALER- A CROSS
SECTIONAL VIEW.
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E. MAGNETICALLY ACTIVATED DRUG DELIVERY SYSTEM
▪ In this type of system, the drug reservoir is a dispersion of peptide or protein powders in a
polymer matrix from which macromolecular drug can be delivered at a relatively slow rate.
▪ Magnetic drug delivery means the specific delivery of therapeutic agents to their desired target
area using magnetic field.
▪ A sub-dermally implantable, magnetically activated drug delivery device is fabricated by
first positioning a tiny magnet ring in the core of a hemispherical drug-dispersing polymer
matrix and then coating its external surface with a drug impermeable polymer such as ethylene-
vinyl acetate copolymer or silicone elastomers, except one cavity at the center of flat surface.
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HEMISPHERIC MAGNETICALLY ACTIVATED DRUG DELIVERY SYSTEMS
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▪ This uncoated cavity is positioned directly above the magnet ring, which permits a
peptide drug to be released.
▪ It is used to deliver protein drugs, such as bovine serum albumin, at a low basal rate, by
a simple diffusion process under non triggering conditions.
▪ As the magnet is activated to vibrate by an external electromagnetic field, the drug
molecules are delivered at a much higher rate.
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F. SONOPHERESIS ACTIVATED DRUG DELIVERY SYSTEMS
• This type of DDS utilizes ultrasonic energy to activate the delivery of drugs
from a polymeric drug delivery device.
• The system can be fabricated from either a non-degradable polymer such as
ethylene-vinyl acetate copolymer or a bioerodible polymer such as poly [bis (p-
carboxy phenoxy) alkane anhydride.
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SONOPHORESIS ACTIVATED DRUG DELIVERY OF MANNITOL- IN RAT INTACT SKIN
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G. IONTOPHORESIS ACTIVATED DRUG DELIVERY SYSTEMS
▪ This type of system uses the electrical current to activate and to modulate the
diffusion of a charged drug molecule, across a biological membrane like the skin,
in a manner similar to passive diffusion under a concentration gradient, but at a
much facilitated rate.
▪ The iontophoresis- facilitated skin permeation rate of a charged molecule i consists
of 3 components and is expressed by,
J isp
i = Jp + Je + Jc
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Where,
𝑑
Jp 𝐶
= PASSIVE SKIN PERMEATION FLUX → Ks Ds ℎ
𝑠
Je 𝑍 𝐷𝑖 𝐹 𝑑𝐸
= ELECTRICAL CURRENT DRIVEN PERMEATION FLUX 𝑖
→ C
𝑅𝑇 i ℎ
𝑠
Jc = CONVECTIVE FLOW DRIVEN SKIN PERMEATION FLUX → K Cs Id
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Where, Ks = partition coefficient for interfacial partitioning from donor solution to
stratum corneum.
Ds = diffusivity across the skin.
Di = diffusivity of ionic species i in the skin.
Ci = donor concentration of ionic species i the skin.
Cs = concentration in skin tissues.
dE/hs = electrical potential gradient across skin.
dC/hs = concentration gradient across skin.
Z i= electrical valence of ionic species i.
Id = current density applied.
F = faraday constant.
K = proportionality constant
T = absolute temperature
R = gas constant
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EXAMPLE:
Phoresor by motion control
To facilitate the percutaneous penetration of anti-inflammatory drugs to surface tissues
EG: DEXAMETHASONE SODIUM PHOSPHATE
DEVELOPMENT:
▪ TPIS – Transdermal Periodic Iontotherapeutic System
▪ Capable of delivering pulse direct current in a periodic manner which is
physiologically acceptable with a special combination of waveform,
intensity, frequency and on/off ration.
▪ Eg: For proteineous drugs → INSULIN.
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TPIS- AN IONTOPHORESIS ACTIVATED DRUG DELIVERY SYSTEM
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H. HYDRATION ACTIVATED DRUG DELIVERY SYSTEM
▪ This type of system depends on hydration induced swelling process to activate
the release of drug.
▪ The drug reservoir is homogeneously dispersed in a swellable polymer matrix
fabricated from hydrophilic polymer.
▪ The release of drug is controlled by the rate of swelling of polymer matrix.
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EXAMPLE: VALRELEASE TABLETS
▪ It is prepared by granulation of homogenous dispersion of Valium (a
tranquilizer) in hydrocolloid and excipients.
▪ The granules are compressed to form tablets.
▪ After oral intake the hydrocolloid in tablet absorbs GI fluid and forms a
colloidal gel that starts from the tablet surface and grows inwards.
▪ The release of Valium molecules is then controlled by matrix diffusion
through this gel barrier.
▪ The tablet remain buoyant in the stomach as a result of the density
difference between the gastric fluid (d >1) and the gelling tablet (d < 1).
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HYDRATION INDUCED FORMATION OF COLLOIDAL GEL BARRIER(VALRELEASE
TABLET) –A HYDRATION ACTIVATED SYSTEM
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CHEMICAL MEANS
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pH ACTIVATED DRUG DELIVERY SYSTEMS
▪ This type of DDS permits the delivery of a drug only in the region with a selected
pH range.
▪ It is fabricated by coating the drug containing core with a pH sensitive
polymer combination.
▪ Gastric fluid labile drug is protected by encapsulating it inside a polymer
membrane that resists the degradative action of gastric pH, such as combination
of ethyl cellulose and hydroxy methylcellulose phthalate
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▪ In stomach, coating membrane resists the action of gastric fluid and the drug molecules
are thus protected from acid degradation.
▪ After gastric emptying the drug delivery system travels to small intestine and intestinal
fluid will activate the erosion of intestinal fluid soluble hydroxy methylcellulose phthalate
component from coating membrane.
▪ This leaves a micro porous membrane of intestinal fluid insoluble polymer of ethyl
cellulose, which controls the release of drug from the core tablet.
▪ The drug solute is thus delivered at a controlled manner in intestine by combination of
dissolution and pore-channel diffusion.
▪ By adjusting the ratio of intestinal fluid soluble polymer to intestinal fluid insoluble
polymer, the membrane permeability of drug can be regulated as desired.
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pH DEPENDENT FORMATION OF MICROPOROUS MEMBRANE IN INTESTINE
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ION –ACTIVATED DRUG DELIVERY SYSTEMS
• An ionic or charged drug can be delivered by ion-activated DDS.
• It is prepared by first complexing an ionic drug with an ion exchange resin containing a
suitable counter ion (Cationic drug with SO –
3 resin, Anionic drug with N(CH +
3)3 resin).
• The granules of drug-resin complex are first treated with an impregnating agent, PEG-
4000, to reduce the rate of swelling in an aqueous environment and then coated by air-
suspension coating, with a water insoluble polymer such as ethyl cellulose.
• This membrane serves as a rate controlling barrier to modulate the influx of ions as well
as the release of drug from the system.
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▪ In electrolyte medium, such as gastric fluid, ions diffuse into system, react with drug-resin
complex and trigger the release of ionic drug.
▪ This system is exemplified by the development of Pennkinetic (by Pennwalt
Pharmaceuticals) which permits the formulation of liquid suspension dosage form with
sustained release drug properties for oral administration.
▪ Since GI fluid regularly maintains a constant level of ions, i.e., constant ionic strength, the
delivery of drug from this system can be maintained at a constant rate relatively.
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ION ACTIVATED DRUG DELIVERY SYSTEM
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HYDROLYSIS ACTIVATED DRUG DELIVERY SYSTEM
▪ This type of activation controlled drug delivery system depends on
hydrolysis process to activate the release of drug molecules.
▪ Here, drug reservoir is either encapsulated in microcapsules or
homogeneously dispersed in microspheres or nanoparticles for injection.
▪ It can also be fabricated as an implantable device.
▪ All these systems are prepared by bioerodable polymer such as co(lactic-
glycolic) polymer, polyorthoester or poly anhydride.
▪ The release of drug from polymer matrix is activated by hydrolysis
induced degradation of polymer chains and controlled by the rate of polymer
degradation.
▪ EX: Development of LHRH releasing biodegradable subdermal implant
designed to deliver goserelin (synthetic LHRH analogue) for once-a-month
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AMINO ACID SEQUENCE OF GOSERELIN, A SYNTHETIC LHRH, AND THE EFFECT OF
SUBCUTANEOUS CONTROLLED RELEASE OF GOSERELIN FROM THE BIODEGRADABLE POLY
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BIOCHEMICAL MEANS
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ENZYME- ACTIVATED DRUG DELIVERY SYSTEMS
▪ This type of activation controlled drug delivery system depends on
enzymatic process to activate the release of drug.
▪ In this system the drug reservoir is either physically entrapped in
microspheres or chemically bound to polymer chains from biopolymer, such
as albumin or polypeptides.
▪ The release of drug is activated by enzymatic hydrolysis of biopolymers by a
specific enzyme in the target tissue.
▪ EX: Development of albumin microspheres that release 5-flurouracil in a
controlled manner by protease activated biodegradation
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FEEDBACK REGULATED DRUG
DELIVERY SYSTEMS
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▪ The release of drug from delivery system is activated by a triggering
agent such as a biochemical substance, in the body and also regulated
by its concentration via some feedback mechanism.
▪ Rate of drug release is controlled by the concentration of triggering
agent detected by a sensor in the feedback regulated mechanisms.
▪ Feedback regulated drug delivery concept was applied to
▪ TYPES:
1. BIOEROSION – REGULATED DDS
2. BIORESPONSIVE – DDS
3. SELF – REGULATING DDS
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BIOEROSION – REGULATED DRUG DELIVERY SYSTEMS
▪ The system consist of drug-dispersed bioerodable matrix fabricated from poly (vinyl
methyl ether) half-ester, which was coated with a layer of immobilized Urease, in a
solution with neutral pH polymer erodes very slowly.
▪ In presence of urea, Urease at the surface of drug delivery system metabolizes urea to
ammonia.
▪ This causes pH to increase and a rapid degradation of polymer matrix as well as the
release of drug molecules.
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BIOEROSION REGULATED DELIVERY OF HYDROCORTISON- A FEEDBACK
REGULATED SYSTEM, A CROSS SECTIONAL VIEW.
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BIORESPONSIVE DRUG DELIVERY SYSTEM
▪ In this system, the drug reservoir is contained in a device enclosed by a
Bio responsive polymeric membrane whose drug permeability is
controlled by the concentration of biochemical agent in the tissue
where the system is located.
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Development of glucose-triggered insulin delivery system in which the insulin reservoir is
encapsulated within a hydrogel membrane having pendant-NR2 groups.
In alkaline solution – NR2 groups are neutral and membrane is unswollen and impermeable to insulin.
As glucose, a triggering agent penetrates into the membrane, it is oxidized enzymatically by glucose
oxidase entrapped in membrane to form gluconic acid.
The -NR2 groups are to protonated to form –NR2H
+, and the hydrogel membrane then becomes
swollen and permeable to insulin molecules.
The amount of insulin delivered is thus Bioresponsive to the concentration of glucose penetrating the
insulin delivery system
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SELF REGULATING DRUG DELIVERY SYSTEMS
▪ This type of feedback regulated drug delivery system depends on a reversible and
competitive binding mechanism to activate and to regulate the release of drug.
▪ In this system the drug reservoir is a drug complex encapsulated in a
semipermable polymeric membrane.
▪ The release of drug from the delivery system is activated by the membrane
permeation of a biochemical agent from the tissue in which the system is
located.
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▪ Reversible binding of sugar molecules by lectin in the design of self regulating drug
delivery system. It first involves preparation of biologically active insulin derivatives in
which insulin is coupled with a sugar (maltose) and this into an insulin-sugar-lectin
complex.
▪ The complex is then encapsulated within a semi permeable 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.
▪ The released insulin-sugar derivatives then diffuse out of the device, and the amount of
insulin-sugar derivatives released depends on the glucose concentration. Thus a self
regulating drug delivery is achieved.
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SITE SPECIFIC DRUG DELIVERY SYSTEMS
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▪ Site specific or Targeted drug delivery system is a special form of DDS, where drug is
selectively targeted or delivered only to its site of action or absorption and not to the
non-target organs, tissues and cells.
▪ The release of drug is activated by the membrane permeation of a biological agent
from the tissue in which the DDS is located.
▪ EXAMPLE: THE MECHANISM OF REVERSIBLE
BINDING OF SUGAR MOLECULES BY LECTIN
➢ It involves preparation of biologically active insulin derivatives in
which insulin is coupled with a sugar(Eg: MALTOSE) to form
insulin – sugar – lectin complex.
➢ This complex is encapsulated within a semipermeable membrane.
➢ Blood glucose diffuse into the device and competitively binds at
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➢ This activated the release of bound insulin – sugar derivatives.
➢ The amount of insulin – sugar derivatives released depends on the blood glucose
concentration, i.e., a self regulatory system.
➢ Drawback: Release of insulin from device in non-linear in response to the
changes in glucose level.
➢ Optimized product: Complex of GLYCOSYLATED INSULIN –
CONCANAVALIN A, which seeks to concentrate the medication in the tissues
of interest while reducing the relative concentration of medication in remaining
tissues.
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The drug may be delivered,
▪ To the capillary bed of the active sites
▪ To the specific type of cell or even an intracellular region.
Ex: Tumor cells but not to normal cells.
▪ To a specific organ or tissue by complexation with the
carrier that recognizes the target.
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CARRIERS OR MARKERS:
▪ Targeted drug delivery can be achieved by using carrier system. Carrier
is one of the special molecule or system essentially required for
effective transportation of loaded drug up to the preselected sites.
▪ They are engineered vectors, which retain drug inside or onto them
either via encapsulation and/or via spacer moiety and deliver it into
vicinity of target cell.
▪ Example: POLYMERS, MICROCAPSULES, MICROPARTICLES,
LIPOPROTIENS, LIPOSOMES AND MICELLES.
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STRATEGIES OF DRUG TARGETING:
1. Passive targeting
2. Inverse targeting
3. Active targeting
4. Ligand mediated targeting
5. Physical targeting
6. Dual targeting
7. Double targeting
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1. Passive targeting – • Drug is targeted to systemic circulation, which occurs due to body’s
natural response to physiochemical properties of drug carrier system.
2. Inverse targeting – • Targeting attempts are made to avoid passive uptake of drug
carrier by RES ( Reticulo Endothelial Systems)
• Done by suppressing normal function of RES.
• By preinjecting large amount of blank colloidal carriers like
DEXTRAN SULPHATE.
• This leads to saturation of RES and suppression of DEFENSE
MECHANISM.
• It is suitable to target drugs to non- RES organs.
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3. Active targeting – Due to surface modifications rather than natural uptake by RES, the
carrier system reaches to specific site.
Modifications include – coating of bio adhesive, non- ionic surfactants
and albumin proteins.
4. Ligand mediated – Achieved by specific mechanisms like,
targeting →Receptor dependent uptake of natural LDL particles.
→Synthetic lipid micro emulsions of partially reconstituted LDL particles
coated with apoprotiens.
5. Physical targeting – Targeting occurs due to environmental changes like pH, ionic
strength, temperature and glucose concentration.
Exception – tumor targeting and cytosolic delivery of genetic
material.
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6. Dual targeting – In this targeting, carrier molecule itself have their own
therapeutic activity and thus increase the therapeutic effect of
drug.
7. Double targeting – Combined system of temporal and special methodologies to target
drug delivery.
Spatial placement relates to specific organs, tissues, cells or even
subcellular compartment.
Temporal delivery refers to controlling the rate of drug delivery to
target site.
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Examples for targeted drug delivery systems:
1. Niosomes Non-ionic surfactant vesicles which can entrap both hydrophilic and
lipophilic drugs either in aqueous or in vesicular membrane.
2. Virosomes They are immunomodulatory liposomes consists of surface
glycoprotein of influenza virus muramyl dipeptide,etc.
3. Cubosomes They are liquid crystalline phase forming small cubic particles suitable for injection.
4. Gold Nano Gold nanoparticle used to develop ultrasensitive detection system
for DNA and protein markers associated with many forms of
cancer.
5. Others Nanotubes, Nanowires, Ufasomes, Nanocrystals, Liposomes, Nanoshells, Nanopores.
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REFERENCES
1. Novel drug delivery system – Y. W. Chien. Published by Marcel Dekkar, inc., New york.
2. Biopharmaceutics and pharmacokinetics- Brahmankar.
3. Fundamentals of controlled release drug delivery- Robinson.
4. Controlled release drug formulation in pharmaceuticals: A study on their properties by Rajesh
Tiwari.
5. Tanmoy Ghosh Drug delivery through osmotic systems published by journal of applied
pharmaceutical science.
6. Overview of controlled release mechanism Ronald A. Siegel and Michael J. Rathbone.
7. Concept & system design of controlled release drug delivery system – by EknathBabu.
T.B(slideshare).
8. A review on controlled drug delivery system by A Harihom Prakash Rao, et al, International Journal
of Pharmacy. 2014; 4(3): 275-282.
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THANK YOU
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