NOVEL DRUG DELIVERY SYSTEMS

QUESTIONS?
•WHAT ARE YOUR EXPECTATIONS????????????
•How this subject is going to be different?
•Any practical applications?
•How do you look forward to convert these
learning as your career opportunities?
•How do we make this subject and learning
interesting?
 End of the session
• Last 15mins – Introduction to few novel products available in the
market.
• Required Information:
• Application
• Competititors
• Mechanism
• Group Discussion on regulatory aspects , if any!!
Activity 1
• Problem Statements?
Digitalization
• Covid Issues Sanitization and hygiene
• Safety of veggies or eatables
• Currency contamination
• Fitness
• Genuine information
• Mental health
• Jobs
• Travel
• Internet issues --
• Water purification
• Biowaste management
• Product Development –
Commercialised
Definition
• Drug delivery refers to approaches, formulations, technologies, and systems
for transporting a pharmaceutical compound in the body as needed to safely
achieve its desired therapeutic effect.
• It may involve scientific site-targeting within the body, or it might involve
facilitating systemic pharmacokinetics; in any case, it is typically concerned
with both quantity and duration of drug presence.
• Drug delivery is often approached via a drug's chemical formulation, but it
may also involve medical devices or drug-device combination products.
• It is highly interdisciplinary.
• Strategies:
• Drug physico-chemical properties
• What is the effect of the drug and system at target site and interactions
• Improvement of drug effect
• Patient comfort and well being
• Why do we need novel drug delivery systems?
Example of unsuitable drugs for
oral SR
• Low absorption in lower intestine
• Very short t1/2
• Long t1/2
• Large dose API
• Poorly soluble API
 Advantages :
1. Less fluctuation in drug blood levels.
2. Frequency reduction in dosing.
3. Improved patient convenience & compliance.
4. Increased safety margin of the high potency drugs.
5. Reduction in total health care cost.
Disadvantages :
1. Decreased systemic availability in comparison to immediate release conventional
dosage forms.
2. Poor in vivo – in vitro correlation.
3. Possibility of dose dumping.
4. Retrieval of drug is difficult.
5. Higher cost of formulation.
 UNIT 1
• Concept & Models for NDDS: Classification of rate controlled drug
delivery systems (DDS), rate programmed release, activation modulated &
feedback regulated DDS, effect of system parameters in controlled drug
delivery

• Computation of desired release rate and dose for controlled release DDS,
pharmacokinetic design for DDS – intermittent, zero order & first order release.

• Carriers for Drug Delivery: Polymers / co-polymers introduction,

• classification, characterization, polymerization techniques, application in CDDS /
NDDS, biodegradable & natural polymers.
 Classification: drug delivery system
Based on their technical sophistication

A. Rate pre programmed DDS B. Activated-modulated DDS

Energy sensor
membrane

Dg reservoir

C. Feedback-regulated DDS D. Site targeting DDS

Biochemical responsive/ Site targeting moiety
Energy sensor
A. Rate pre programmed DDS
In this group , the release of drug molecule from
the system has been preprogrammed at specific
rate profile.
• Polymer membrane permeation
• Polymer matrix diffusion
• Micro-reservoir partition
1.Polymer membrane permeation-controlled drug
delivery system
In this type, drug is totally or partially encapsulated within drug
reservoir.
Its drug release surface is covered by a rate-controlling polymeric
membrane having a specific permeability.
Drug reservoir may exist in solid, suspension or solution form.

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 The rate of drug release is defined by,
Q = Km/r Ka/m DdDm x CR
t Km/r Dmhd + Ka/m Ddhm
Where,

Km/r & Ka/m = partition coefficient of the drug molecule

from reservoir to rate controlling membrane & from
membrane to aq. Layer respectively.
Dd & Dm = diffusion coefficient of rate controlling membrane &
aqueous diffusion layer respectively.
hm & hd = thickness of rate controlling membrane &
aqueous diffusion layer respectively.
CR – drug conc. In reservoir compartment.

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 Ex. Progestasert IUD • The drug reservoir is a suspension of
progesterone & barium sulphate in silicone
medical fluid & is encapsulated in the vertical
limb of a T-shaped device walled by a non-
porous membrane of ethylene-vinyl acetate
co-polymer.
• It is designed to deliver natural progesterone
continuously in uterine cavity at a daily
dosage rate of at least 65 μg/day to achieve
contraception for 1 year.
• Eg 2:
• Bayer

• Skyla, Kyleena etc

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 Transderm-Nitro

NTG-Lactose in silicone fluid

EVA copolymer
silicone adhesive

NTG: 0.5mg/cm2/day

0.25 ng/ml

0.2 ng/ml Estraderm: for postmenoposal

syndrom
estradiol t/d (3-4 day)

Transderm-Scop:
Scopolamine t/d 72hr

25 h
2. Polymer matrix diffusion-controlled drug delivery system
In this type, drug reservoir is prepared by homogeneously dispersing drug particle in rate
controlling polymer matrix from either a lipophilic or a hydrophilic polymer.
The drug dispersion in the polymer matrix is accomplished by either,
1) Blending therapeutic dose of drug with polymer or highly viscous base polymer, followed
by cross linking of polymer chains.
2) Mixing drug solid with rubbery polymer at elevated temp.
3) Dissolving drug and polymer in common solvent followed by solvent evaporation

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 The rate of the drug release from this system,
Q = (2ACRDp)1/2
t
Where,
Q/t1/2 - rate of release of drug
A – initial drug loading dose in the polymer matrix
CR – drug solubility in polymer
Dp – diffusivity of drug in polymer matrix

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Lipophilic polymer Hydrophilic polymer
Non swellable matrix Swellable matrix

Gel layer
Drug depletion zone
 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.

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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.

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3.Microreservior partition-controlled drug delivery
system
In this type, drug reservoir is fabricated by micro dispersion of an aqueous
Suspension of drug in biocompatible polymer to form homogeneous dispersion.
Depending upon the physicochemical properties of drugs & desired rate of drug
release, the device can be further coated with a layer of biocompatible polymer
to modify the mechanism & the rate of drug release.

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 The rate of drug release is defined by,
dQ = DpDdmKp
dt
[
nSp – DlSl(1-n) 1 + 1
kl Km
( ( ]
Dphd + DdhpmKp hl
Where,
n = the ratio of drug conc. At the inner edge of the interfacial barrier over the drug
solubility in the polymer matrix.
m = a/b, a – ratio of drug conc. In the 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 drug
solubility in the same polymer.

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Kl, Km & Kp = partition coefficient for the interfacial partitioning of the drug from the liquid
compartment to the polymer matrix, from the polymer matrix to the polymer-coating
membrane & from the polymer coating membrane to the elution solution respectively.

Dl, Dp & Dd = diffusivities of the drug in the lipid layer surrounding the drug particle, the
polymer coating membrane enveloping the polymer matrix, & the hydrodynamic diffusion
layer surrounding the polymer coating membrane with the thickness hl, hp & hd.

Sl & Sp = solubilities of the drug in the liquid compartments & in the polymer matrix,
respectively.

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Release of drug molecules from this type of system can follow either a
dissolution or a matrix diffusion controlled process depending upon the
relative magnitude of Sl & Sp.

Release of drug molecule is controlled by,

Partition coefficient

Diffusivity of drug

Solubility of drug

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B. Activation modulated drug delivery system

• In this group of controlled release drug delivery

system, the release of drug molecules from the
delivery system is activated by some physical,
chemical, or biochemical process and/or by energy
supplied externally.

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 B. Activation modulated

1. Physical means 2. Chemical means 3. BioChemical means

1. pH activated
2. Ion activated
1. Osmotic pressure activated
3. Hydrolysis activated
2. Hydrodynamic pressure activated
3. Vapor pressure activated 1. Enzyme activated
4. Mechanically activated 2. Biochemical activated
5. Magnetically activated
6. Sonophoresis activated
7. Iontophoresis activated
8. Hydration activated
1. Physical means
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.

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Osmotic pressure
For DDS containing a solution formulation

Q PW Am
= (лS - лe)
t hm

For DDS containing a solid formulation

Q PW Am
= (лS – лe) Sd
t hm
Where,
Q/t - rate of drug release
Pw - permiability of semipermiable housing
Am -effective S.A. of semipermiable housing
hm - thickness of semipermiable housing
( ps - pe) – differential osmotic pressure between the drug delivery system
with osmotic pressure ps & the environment with osmotic presure pe.
Sd – aqueous solubility of the drug contained in the solid formulation.

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 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.
Eg. Alzet osmotic pump

Concept: https://www.youtube.com/watch?v=QOOQ5pOZyWU
Surgical procedure :
https://www.youtube.com/watch?v=hGefoX0n8n0

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Basic components
• Drug
• Osmogen or osmotic driving agent
• Semi permeable membrane
• Matrix core
• Wicking agents
• Solubilizing agents
• Coating polymers solvents
• Plasticizers
• Flux regulators
• Pore forming agents
 OSMOGEN / OSMAGENT / OSMOTIC DRIVING
AGENT
• For the selection of osmogen , the two most critical properties to be
considered are osmotic activity and aqueous solubility .
• Osmotic agents are classified as,
• Inorganic water soluble osmogens : Magnesium sulphate , Sodium
chloride, Sodium sulpahte , Potassium chloride, Sodium bicarbonate etc.
• Organic polymeric osmogens : Na CMC, HPMC, HEMC, etc. Organic
water soluble osmogens : Sorbitol , Mannitol,etc
 SEMIPERMEABLE MEMBRANE
• Semipermeable membrane must possess certain performance criteria:
• It must have sufficient wet strength and water permeability.
• It should be selectively permeable to water and biocompatible.
• Cellulose acetate is a commonly employed semipermeable membrane for the
preparation of osmotic pumps.
• Some other polymers such as agar acetate, amylose triacetate, betaglucan acetate, poly
(vinyl methyl) ether copolymers, poly ( orthoesters ), poly acetals , poly (glycolic acid)
and poly (lactic acid) derivatives.
• The unique feature of semipermeable membrane utilized for an osmotic pump is that it
permits only the passage of water into the unit, thereby effectively isolating the
dissolution process from the gut environment.
HYDROPHILIC AND HYDROBHOBIC POLYMERS
• These polymers are used in the formulation development of osmotic systems
containing matrix core.
• The selection of polymer is based on the solubility of drug as well as the amount and
rate of drug to be released from the pump.
• The highly water soluble compounds can be co-entrapped in hydrophobic matrices
and moderately water soluble compounds can be co-entrapped in hydrophilic
matrices to obtain more controlled release.
• Examples of hydrophilic polymers are Hydroxy ethyl cellulose, carboxy methyl
cellulose, hydroxyl propyl methyl cellulose, etc. Examples of hydrophobic polymers
are e thyl cellulose, wax materials , etc.
Wicking Agents
• It is defined as a material with the ability to draw water into the
porous network of a delivery device.
• The function of the wicking agent is to draw water to surfaces inside
the core of the tablet, thereby creating channels or a network of
increased surface area.
• Examples: Collodion silicon dioxide, kaolin, titanium dioaxide,
alumina, SLS, low molecular weight PCP, bentonite, magnesium
aluminum silicate etc.
Flux Regulators

• Flux regulating agents or flux enhancing or decreasing

agents that are added to the walk forming materials.
• It assist in regulating the fluid permeability through the
membrane
• Polyhydric alcohols
• Eg: poly alkylene glycols and low molecular glycols,Poly
butylene etc.
 Pore forming agents
• Agents that are used in the pumps for poorly water soluble drug and in
the development of controlled porosity of multiparticulate osmotic
pumps.
• Pore formers can be inorganic or organic and in solid or liquid nature.
• Eg: Alkaline metal salts such as sodium chloride, sodium bromide,
potassium chloride
• Alkaline earth metals like calcium chloride and calcium nitrate
• Carbohydrates like glucose, fructose etc.
 Classification of Osmotic Pumps:
• ORAL Osmotic Pumps
• IMPLANTABLE Osmotic Pumps
 Type of Implantable Osmotic Pumps:
• FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSON OSMOTIC PUMP):
• ELEMENTARY OSMOTIC PUMP (EOP):
• ELEMENTARY OSMOTIC PUMP (EOP) Rose Nelson pump was further
simplified in the form of elementary osmotic pump (by Theeuwes,1975)
which made osmotic delivery as a major method of achieving controlled
drug release.
• ELEMENTARY OSMOTIC PUMP (EOP) :
• ELEMENTARY OSMOTIC PUMP (EOP) Core containing agent Delivery Orifice
Semi permeable membrane
• 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. This pump eliminates
the separate salt chamber unlike others.
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 non-extensible 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 the small orifice.
The process continues at a constant rate till the entire solid drug inside the tablet is
eliminated leaving only solution filled shell.
This residual dissolved drug is delivered at a slower rate to attain equilibrium
between external and internal drug solution.
• LIMITATION OF EOP:
• LIMITATION OF EOP Generally in osmotic pumps the semi permeable
membrane should be 200-300 μ m thick to withstand pressure with in the
device.
• These thick coatings lower the water permeation rate, particularly for
moderate and poorly soluble drugs.
• In general we can predict that these thick coating devices are suitable for
highly water soluble drugs. This problem can be overcome by using coating
materials with high water permeabilities .
• For example, addition of plasticizers and water soluble additive to the
cellulose acetate membranes, which increased the permeability of membrane
up to ten fold .
• Controlled Porosity Osmotic Pump (CPOP) :
• Controlled Porosity Osmotic Pump (CPOP) : The delivery orifice is formed
by incorporation of a leachable water-soluble component in the coating
material Drug release from the whole surface of device rather than from a
single hole which may reduce stomach irritation problem
• The semi permeable coating membrane contains water-soluble pore forming
agents like NaCl , KCl , and Urea .
• Such formed pores becomes permeable for both water and solutes .
• The release rate from these types of systems has been reported to be
dependent on :
• the coating thickness (20-500 𝜇m)
• level of soluble components in the coating solubility of the drug in the tablet core
• osmotic pressure difference across the membrane (8-500 atm ) but
• independent of the pH and agitation of the release media
• Ex. Chitosan-based controlled porosity osmotic pump (Citric Acid as pore
forming) for colon-specific delivery system: screening of formulation
variables and in vitro investigation : microbially triggered colon-targeted
osmotic pump (MTCT-OP)
• The gelable property at acid condition and colon-specific biodegradation of
chitosan
 Multichamber osmotic pump :
• Multichamber osmotic pump Push Pull Osmotic System (PPOP) :
• They contain two or three compartment separated by elastic
diaphragm Upper compartment contain drug with or without
osmogen (drug compartment nearly 60 – 80 %) and lower
compartment (Push compartment) contain Osmogen at 20 –
40 %.
• It is a bilayer tablet coated with semi permeable membrane.
Example Procardia XL for Nifedipine
 Sandwiched Osmotic tablets (SOTS):
• Sandwiched Osmotic tablets (SOTS) It is composed of polymeric push
layer sandwiched between two drug layers with two delivery orifices.
• When placed in the aqueous environment the middle push layer
containing the swelling agents, swells and the drug is released from the
delivery orifices.
• Advantage : the drug is released from the two orifices situated on
opposite sides of the tablet.
 OROS Capsules OROS- CT:
• OROS Capsules OROS- CT It is developed by Alza co-operation.
• It is used as a once or twice a day formulation for targeted delivery of
drugs to the colon.
• It consist of
• an enteric coat, SPM & core.
• Core consist of two compartments - one compartment consist of drug near to
orifice.
• Second compartment consist of osmopolymer
• The OROS-CT can be a single osmotic agent or it can be comprise of as
many as five to six push pull osmotic unit filled in a hard gelatin capsule.
• L-OROS:
• L - OROS Liquid OROS controlled release systems are designed to continuous deliver
drugs as liquid formulations.
• A liquid formulation is used for delivering insoluble drugs and macromolecules.
• Such molecules require external liquid components to assist in solubilization ,
dispersion, protection from enzymatic degradation and promotion of gastrointestinal
absorption.
• It combines the benefits of extended-release with high bioavailability.
• These are of two types -: - L-OROS Soft cap - L-OROS Hard cap
• L-OROS Soft cap:
• The liquid drug formulation is present in a soft gelatin capsule, which is surrounded
with the barrier layer, the osmotic layer, and semi permeable membrane.
• A delivery orifice is formed through these three layers.
• When the system is in contact with the aqueous environment, water is imbibed &
results in the development of osmotic pressure inside the system forcing the liquid
formulation to break through the hydrated gelatin capsule shell at the delivery
orifice
• L-OROS Hard Cap:
• L-OROS Hard Cap Another type of L-OROS system consists of a hard
gelatin capsule containing a liquid drug layer, a barrier layer and a push
layer surrounded by a semipermeable membrane.
• The L-OROS hardcap system was designed to accommodate more
viscous suspensions with higher drug loading than would be possible
using softcap design.
• Rate controlling membrane Push layer Inner Capsule Delivery orifice
Inner Compartment Barrier layer
Implantable osmotic pump:
Implantable osmotic pump Implantable systems further classified as-:
1. For experimental use
2. For human use
For experimental use -:
ALZET ® It is a miniature, implantable osmotic pumps for laboratory animals.
The pump are used to deliver homogenous solutions or suspensions
continuously at a controlled rate for extended period.
It consist of Drug reservoir, osmotic sleeve & semipermeable membrane.
ALZET® osmotic pump:
Design: Empty reservoir within the core of the pump is filled with the drug
or hormone solution to be delivered and is surrounded by salt chamber
with impermeable layer between them.
Mechanism: Water enters into the salt chamber through semipermeable
membrane and causes compression of flexible reservoir and delivery of
drug solution.
Application: To deliver drugs, hormones, and other test agents
continuously at controlled rates from one day to six weeks.
• ALZET OSMOTIC PUMP ADVANTAGES
• Ensure around-the-clock exposure to test agents at predictable levels .
• Permit continuous administration of short half-life proteins and
peptides.
• Convenient method for chronic dosing of laboratory animals. Minimize
unwanted experimental variables and ensure reproducible, consistent
results.
• Eliminate the need for nighttime or weekend dosing. Reduce handling
and stress to laboratory animals.
• Small enough for use in mice or very young rats.
• Allow for targeted delivery of agents to virtually any tissue.
• Cost-effective research tool
• DUROS® osmotic pump:
• DUROS ® osmotic pump
• Design : Implantable drug-dispensing osmotic pump, shaped as a small
rod with titanium housing.
• Mechanism : Through osmosis, water from the body is slowly drawn
through the semi-permeable membrane into the pump by osmotic
agent residing in the engine compartment, which expands the osmotic
agent and displaces a piston to dispense small amounts of drug
formulation from the drug reservoir through the orifice.
• Application: Systemic or site-specific administration of a drug
• DUROS®:
• DUROS ® DUROS ® implants are designed to bring the benefit of
continuous therapy for up to one year.
• The non-biodegradable, osmotically driven system is intended to enable
delivery of small drugs, peptides, proteins, DNA and other bioactive
macromolecules for systemic or tissue-specific therapy.
• Viadur ® ( leuprolide acetate implant), the first marketed product to
incorporate DUROS ® , is indicated for the palliative treatment of
advanced prostate cancer.
• ADVANTAGES Can deliver highly concentrated and viscous formulations.
Improved patient compliance Titanium protects the drug from
enzymatic degradation.
• The system can be engineered to deliver a drug at a desired dosing rate
with high degree of precision.
 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.

91
 In the GIT, the laminate absorb the GI fluid through the annular
openings at the lower end of the housing & becomes
increasingly swollen, which generates hydrodynamic pressure in
the system.
Rate of drug release is defined by,
Q = Pf Am ( qs - qe)
t hm
Where,
Pf = fluid permeability
Am = effective Surface area
hm = thickness of wall with anular opening
(qs - qe) = differential hydrodynamic pressure between the drug delivery
system & the environment.
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Rate controlling factors :
Fluid permeability
Effective surface area of the wall with the annular opening.
Hydrodynamic pressure gradient.

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 Vapor pressure-activated drug delivery system

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 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.

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 The rate of drug release is defined by,
Q = d4 (Ps -Pe)
t 40.74 ml
Where-
Q/t - rate of drug release
d – inner diameter of cannula
l – length of cannula
(Ps -Pe)- the difference between the vapor pressure in the vapor chamber &
pressure at the implantation site.
m - viscosity of the drug solution.

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 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.

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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.

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Ex. Metered-dose inhaler

the volume of solution delivered is

controllable, as small as 10-100 ml & is
independent of the force & duration of the
activation applied as well as the solution
volume in the container.

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Magnetically activated drug delivery system
Design

Fabrication

Drug used: BSA (Subdermal Implant)

EVA/ SE
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.
Device is fabricated by positioning a tiny magnet ring in core of
hemispherical drug dispersing polymer matrix.

102
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.

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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]
The potential application of sonophoresis to regulate the delivery of drugs
was recently reviewed.

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 Iontophoresis activated drug delivery system

This type of system uses electrical current to activate & to modulate the
diffusion of charged drug across biological membrane.

Iontophoresis – facilitated skin permeation rate of charged molecule (i)

consist of 3 components & is expressed by,

Jiisp = Jp + Je +Jc

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Where,
Jp – passive skin permeation flux.
= KsDs dC
hs
Ks = partition coefficient for interfacial partitioning from donor solution to
stratum corneum
Ds = diffusivity across the skin
dC = concentration gradient across the skin
hs
Je – electrical current driven permeation flux
= ZiDiF Ci dE
RT hs
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 Zi = electric valency of the ionic species i
Di = diffusivity of ionic species i in the skin
F = faraday constant
T = absolute temperature
Ci = donor conc. of ionic species i in the skin
dE = electrical potential gradient across the skin
hs

Jc = convective flow driven skin permeation flux

= k Cs Id
Where,
K = proportionality constant
Cs= conc. In the skin tissue
Id = current density applied

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Activation by electric current Facilitated passive diffusion
Schematic diagram illustrating the principles of
iontophoresis.
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 Valrelease®

Hydration activated drug delivery system

Hydrophilic polymer

Lipophilic polymer

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.
2. Chemical means : pH activated DDS

Not just activation but targeting also

Porous or eroded layer

 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.
For instances, a gastric fluid labile drug is protected by encapsulating it inside
a polymer membrane that resist the degradative action of gastric pH.

112
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.

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Chemical means
Ion activated DDS
Drug-resin granule

PG coating 4K

EC coating

Pennkinetic
Ion- activated drug delivery system

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 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(CH3)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.

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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.
 Chemical means
Hydrolysis activated DDS
• Bioerodible or biodegradable polymer
• Co(L-G), POE, PAn etc

micrpores

Sub dermal implant

LHRH
 Hydrolysis- activated drug delivery system
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.

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 It can also be fabricated as an implantable device.
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.
Ex. LHRH – releasing biodegradable subdermal implant, which is designed to
deliver goserline, a synthetic LHRH analog for once a month treatment of
prostate carcinoma.

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3 BioChemical means
Enzyme activated DDS
Reservoir may be physically entrapped and chemically bonded
Enzymatic hydrolysis of biopolymer
Ex: 5-FU----- albumin (microspheres)

Protease
 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 – fluorouracil in a controlled manner by
protease – activated biodegradation.

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 C.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.

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 They are further classified as

i. Bioerosion-regulated drug delivery system

ii. Bioresponsive drug delivery system

iii. Self-regulating drug delivery system

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I. Bioerosion-regulated drug delivery system
This system was developed by
Heller & Trescony.
The system consisted of drug-
dispersed bioerodible matrix
fabricated from poly (vinyl methyl
ether) ester which is coated with
layer of immobilized urease.

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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.

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 II. 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.

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 Ex. – glucose-triggered insulin drug delivery system.

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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.

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 III.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.

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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.

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D. Site targeting DDS
Ringsdorf, 1978
It is constructed from Non-immunogenic and
Biodegradable polymer backbone with 3 functional
group attached.

1.Site specific targeting moiety

2.Solubilizer that unable DDS to transported to target
tissue
3.Drug moiety covalently bonded to polymer backbone
though spacer and contains cleavable group that can
be cleaved by specific enzyme at target site
 Effects of system parameters
Polymer solubility
Solution solubility
Partition coefficient
Polymer diffusivity
Solution diffusivity
Thickness of polymer diffusional path
Thickness of hydrodynamic diffusion layer
Drug loading dose
Surface area
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 Polymer diffusivity (Dp)
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 Ed, has been acquired by the diffusant & it’s surrounding polymer
matrix.

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 This energy- activated diffusion process is frequently described by the
following Arrhenius relationship :

Dp = D0 e-(Ed/RT)

The bulkier the functional group attached to polymer chain lower the
polymer diffusivity.

Magnitude of polymer diffusivity is dependant upon type of functional group

and type of stereo chemical position in diffusant molecule.

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Polymer diffusivity also depends on

1) Effect of cross linking

2) Effect of crystallinity

3) Effect of fillers

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 Solution diffusivity (Ds)
• 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.
• The diffusivity of the solute molecules in the aqueous solution whose molar volume
is equal to or greater than the molar volume of water molecules is inversely
proportional to the cube root of their volume.

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When solution diffusivity are compared on bases of molecular volume,
alkanes are most rapidly diffusing chemicals.

The relative rates of diffusion of various chemical classes are as follows :

alkane > alcohol > amides > acids > amino acids > dicarboxylic acid

Diffusivity of solute molecule in aqueous solution usually decreases as its

concentration increases.

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 Thickness of polymer diffusional path (hp)
Control release of drug species from both polymer membrane & polymer
matrix controlled drug delivery system is governed by,
1) The solute diffusion coefficient in the membrane lipid.
2) The thickness of the membrane.

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• hp value for polymer membrane controlled reservoir devices, which are
fabricated from non biodegradable and non swollen polymer, the value is
defined by polymer wall with constant thickness that is invariable with time
span.

• In polymer matrix controlled reservoir devices, which are fabricated from non
biodegradable polymers, the thickness of diffusional path is defined as drug
depletion zone progressively in proportion to the square root of time.

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 The rate of growth in the hp value can be defined
mathematically by :
hp 2CpDp 1/2
= (
t1/2 ( A – C /2
p

Where,
Cp = solubility of drug in the polymer phase
Dp = diffusivity of drug in the polymer matrix
A = loading dose of a drug

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Thickness of hydrodynamic diffusion layer (hd)
The hydrodynamic diffusion layer has a rate limiting role on controlled release
dosage form.

Magnitude of drug release value decreases as the thickness of hydrodynamic

diffusion layer is increased.

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 Polymer solubility
• Drug particles are not released until they dissociate from their crystal lattice
structure, dissolve or partition into surrounding polymer.
• Solubility of drug in polymer membrane or matrix plays important role in it’s
release from a polymeric device.
• For a drug 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.

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 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.
By using a water – miscible co-solvent as a solubilizer & addition of the co-solvent
into the elution solution to increase the solution solubility of drugs.
• Solubilization of poorly soluble drug in aqueous solution can be accomplished by
using multiple co-solvent system.
• Drug release increases with increase in Solution solubility of drug.
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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 = Cs/Cp
Where,
Cs = conc. Of drug at the solution/polymer interface
Cp = solubility of drug in the polymer phase.

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Ratio of drug solubility in the elution solution Cs over its solubility in polymer
composition Cp of device.
Any variation in either Cs or Cp result in increase or decrease in magnitude
of ‘K’ value.
Rate of drug release increase with increase in partition coefficient.

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 Drug loading dose
In preparation of the device varying loading doses of drugs are
incorporated, as required for different length of treatment.

Variation in the loading doses results only in the change in duration of

action with constant drug release profile.

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 Surface Area

Both the in-vivo & in-vitro rates of drug release dependant on the
surface area of the drug delivery device.

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

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References
Novel drug delivery system- Y.W.Chien.

Fundamentals of controlled release drug delivery- Robinson.

Web – www.google.com

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