Controlled Drug Delivery System: Dr. Basavaraj K. Nanjwade

Controlled Drug Delivery System
Dr. Basavaraj K. Nanjwade

KLE University’s College of Pharmacy
BELGAUM- 590010, India
E-mail: bknanjwade@yahoo.co.in
Cell No: 0091 9742431000
“Ideal” Drug Delivery
System
• Inert
• Biocompatible
• Mechanically strong
• Comfortable for the patient
• Capable of achieving high drug loading
• Readily processable
• Safe from accidental release
• Simple to administer and remove
• Easy to fabricate and sterilize
• Free of leachable impurities
09/08/2010 KLE COP, NIpani 2

Modified Drug Release
 Release can be:

• instantaneous (delayed-release)
• zero-order process (sustained release -
mostly non-oral)
• first-order process (oral extended
release)

Terminology
 Sustained release:
• any dosage form that provides medication
over an extended time
• timed release, prolonged release etc
 Controlled release:
• denotes that the system is able to provide
some actual therapeutic control, whether
this be of a temporal nature, spatial nature,
or both

Traditional vs. Controlled
Release Drug Dosing

Traditional vs. Controlled
Release
 With traditional administration, the drug active

must remain between a maximum blood level
value which may represent a toxic level and a
minimum value below which the drug is no longer
effective
 With controlled administration, the blood levels

are constant between the desired maximum and
minimum for an extended period of time

Controlled Drug Delivery
 Controlled drug delivery occurs when a

polymer is combined with a drug or
active agent such that the release from
the bulk material is pre-designed.
• not all controlled systems are sustaining
• targeted drug delivery
• prodrugs, others

Advantages of
 Eliminate over or underdosing

 Maintain drug levels in desired
range
 Need for less dosing
 Increased patient compliance
 Prevention of side effects

Design of Controlled
Drug Delivery
 Biopharmaceutic Characteristics of the Drug

Molecular weight, Aqueous solubility, Partition coefficient,
Drug Pka and Ionization, Route of administration, Drug
stability etc
 Pharmacokinetic Characteristics of the Drug
Absorption rate, Elimination Half-Life, Rate of metabolism etc.
 Pharmacodynamic Characteristics of the Drug

Therapeutic Range, Therapeutic index, Plasma concentration
response relatioship

Depending on the formulation and the application,

the time of release can be quite varied
• Procardia XL - 24 hours

• Lupron Depot - 1 month

• Norplant - 5 years

Polymers for Controlled
Release
These are some of the first materials selected for

delivery systems bases on their intended non-
biological physical properties:
• Polyurethanes for elasticity
• Polysiloxanes for insulating ability
• Polymethyl methacrylate for physical strength and
transparency
• Polyvinyl alcohol for hydrophilicity and swelling
• Polyvinyl pyrrolidone for suspension capabilities

Current Polymers used in
These polymers became usable in controlled

delivery due to their inert physical characteristics
and being free of leachable impurities
• Poly 2-hydroxy ethyl methacrylate

• Poly N-vinyl pyrrolidone
• Polyvinyl alcohol
• Polyacrylic acid
• Polyethylene glycol
• Polymethacrylic acid

Oral Dosage Form
 Biological Factors
• Half-life
• Absorption
• active vs passive
• GI transit time
• floating systems
• bioadhesives
• penetration enhancers
• Metabolism
Oral Dosage Form
 Physicochemical Factors
• Dose Size (0.5-1.0 g)
• Ionization, pKa and aqueous
solubility
• solubility less 0.01 mg/ml (digoxin,
griseofulvin)
• Partition Coefficient
• Stability

Diffusion-Controlled
Systems
 Reservoir Devices

Characteristics of a Reservoir
Diffusional Systems
 Advantages
• zero-order delivery is possible
• release rate variable with polymer type
 Disadvantages
• removal of system from implants
• bad for high-molecular weight
compounds
• cost
• potential toxicity if system fails

Reservoir Diffusional
Products
PRODUCT MANUFACTURER
Nico-400 Jones
Nitro-Bid Marion
Nitrospan Rorer

Matrix Devices
 consists of drug dispersed homogeneously

throughout a polymer matrix.
 Drug in the outside layer is exposed to the
bathing solution is dissolved and diffuses
out of the matrix.
 This process continues with the interface
between bathing solution and the solid drug
moving toward the interior.

Matrix Diffusional System

Characteristics of Matrix
Diffusion Systems
 Advantages
• easier to produce than reservoir
devices
• can deliver high molecular-weight
compounds
 Disadvantages
• cannot obtain zero-order release
• removal of remaining matrix is
necessary for implanted systems
Matrix Diffusional
Products
Product Manufacturer
Procan SR Parke-Davis
Desoxyn-Gradumet Abbott
Choledyl SA Parke-Davis

Dissolution-Controlled
Systems
 alternating layers of rate-controlling coats

 group of beads with different coatings
• (Spansule, SmithKline Beecham)
• dC/dt = kd*A(Cs-C) = D/h*A(Cs-C)
• dC/dt=dissolution rate, kd=dissolution
rate const
• D=diffusion coefficient, Cs=saturation
solubility
• C=concentration of solute in bulk
solution

Types of Dissolution
Controlled Systems
Two types of dissolution-
controlled, pulsed delivery
systems
A: Single bead-type device
with alternating drug and rate
controlling layer
B: Beads containing drug

with differing thickness of
dissolving coats

Encapsulated
Dissolution Products
Product Active Ingred Manufacturer

Ornade Spansules PPA, chlorphen. SKB
Contact PPA, others SKB
Diamox Sequels Acetazolamide Lederle(WA)
Chlor-Trimeton Chlorphen. Schering

Repetabs

Matrix Dissolution
Products
Product Active Ingred. Manufacturer
Dimetapp Bromphen. Robins
Extentabs
Donnantal ..... Robins
Extentabs
Quinidex Quinidine Robins
Extentabs
Tenuate Dospan Diethylprop. Merrel

Bioerodible and Combination
Diffusion and Dissolution System
 Strictly speaking, therapeutic systems will never be dependent

on dissolution only or diffusion only.
 Bioerodibile devices, however, constitute a group of systems
for which mathematical descriptions of release is complex.
 The complexity of the system arises from the fact that, as the
polymer dissolves, the diffusion path length for the drug may
change. this usually results in a moving-boundary diffusion
system.
 Zero-order release can occur only if surface erosion occurs
and surface area does not change with time.
 The inherent advantage of such a system is that the
bioerodible property of the matrix does not result in a ghost
matrix.

Representation of a
Bioerodible Matrix System
Drug is dispersed in the

matrix before release at
time = 0. At time = t,
partial release by drug
diffusion or matrix
erosion has occurred

Characteristics of
Bioerodible Matrix Systems
 Advantages
• all the advantages of matrix dissolution
system
• removal from implant sites is not
necessary
 Disadvantages
• difficult to control kinetics owing to
multiple processes of release
• potential toxicity of degraded polymer

Bioerodible and Biodegradable
Controlled Release Polymers
These polymers are designed to degrade

within the body
• Polylactides (PLA)
• Polyglycolides (PGA)
• Polylactide-co-glycolides (PLGA)
• Polyanhydrides
• Polyorthoesters

Degradation of
Biodegradable Polymers
These materials degrade within the body as a result

of natural biological processes, eliminating the need
to remove a drug delivery system after release of the
active agent has been completed
 Bulk hydrolysis - the polymer degrades in a fairly uniform

manner throughout the matrix
 Surface Eroding - degradation occurs only at the surface of

the polymer, resulting in a release rate that is proportional
to the surface area of the drug delivery system

Biodegradable Polymers
Drug delivery from

(a) bulk-eroding and
(b) surface-eroding
biodegradable systems.

Biodegradable (surface eroding)
Polyorthoester rods after (left) 9 weeks
and (right) 16 weeks of implantation
Drug delivery from

(a) bulk-eroding and
(b) surface-eroding
biodegradable systems.

Major Companies Involved in
Polymeric Delivery Technology
• Alza - DUROS, OROS

• Alkermes Inc - Ring Caps
• Nobex Corp. - Drug/Polymer
Conjugates
• Elan - MODAS, PRODAS
• Andrx - SCOT, DPHS

Osmotically Controlled
Systems
• osmoticpressure provides the driving force to
generate controlled release of drug.
• Consider a semipermeable membrane that is
permeable to water, but not to drug. When this
device is exposed to water or any body fluid, water
will flow into the tablet owing to the osmotic
pressure difference.
dV/dt= Ak/h(P)
k=membrane permeability, A=area of the membrane, h=membrane
thickness
 = osmotic pressure difference, P =hydrostatic pressure difference

Types of Osmotically
Controlled Systems
Type A contains a osmotic

core with drug
Type B contains the drug

solution in a flexible bag,
with the osmotic core
surrounding

Types of Osmotically
Controlled Systems

Immediate Release Oxybutynin
V/s Controlled Release Ditropan XL

Characteristics of Osmotically
Controlled Devices
 Advantages
• Zero-order release is obtainable
• reformulation is not required for different drugs
• release of drug is independent of environment of
the system
 Disadvantages
• systems can be very expensive
• quality control is more extensive

Examples of Osmotic
Pump Systems
 Acutrim Appetite suppressant

 Concerta ADHD
 Procardia Hypertension/angina
 Volmax Bronchiodilator
 Ditropan Overactive bladder
Hydrodynamic Pressure
Controlled Systems
• Hydrodynamic pressure generated by swelling of a hydrophilic

gum
• The device comprises of a rigid, shape retaining housing
enclosing a collapsible, impermeable containing liquid drug
• The gun imbibes water in GIT through an opening at the lower
side of external housing and swells creating an hydrodynamic
pressure
• The pressure thus created squeeze the collapsible drug
reservoir to release the medicament through the delivery orifice

Delayed Transit Release
Systems
• Altered Density Systems
High Density Pellets
Low Density Pellets
 Mucoadhesive Systems
Cross linked Polyacrylic acid tablet
 Intestinal Release Systems
Peyer’s patches – Proteins, Peptides, Antigens
 Colonic Release Systems
pH sensitive bioerodiable polymer polymethacrylates
Divinylbenzene cross linked polymers – azoreductase of
colonic bacteria

Ion-Exchange Systems
• Ion-exchange systems generally use resins

composed of water soluble cross-linked polymers
• These polymers contain salt forming functional
groups in repeating position on the polymer chain
• The drug is bound to the resin and released by
exchanging with appropriately charged ions in
contact with the ion exchange groups
Resin+ - drug- + X- resin+ - X- + drug-
Where X- are ions in the GI tract

Different Novel Drug Delivery
Systems
 Microspheres, Liposomes, Niosomes

 Implants
 Pharmacosomes
 Nanoparticles
 Polymeric Films
 Local drug delivery systems, etc

Classes of Drugs for Novel
Drug Delivery
 Anti-cancer agents
 Anti-hypertensive agents
 Anti-psychotic agents
 Non steroidal anti-inflammatory agents
 Anti infective agents
 Anti-diabetic agents
 Protein and peptide drugs
 Biotechnological products
Routes of Administration
 Peroral Route
 Parenteral Route
 Subdermal implants
 Buccal Administration
 Occular Delivery
 Transdermal delivery
 Pulmonary Drug Delivery
 Nasal delivery
 Colon drug delivery
Parenteral Controlled
Release Systems
A. Injectables
Solutions
Dispersions
Microspheres and Microcapsules
Nanoparticles and Niosomes
Liposomes and Pharmacosomes
Resealed erythrocytes
B. Implants
C. Infusion Devices
Osmotic Pumps (Alzet)
Vapor Pressure Powered Pumps (Infusaid)
Battery Powered Pumps

Infusaid Model 400
Implantable Pump

Bone Implants

Administration of Implant to
Rabbit Femur

Transdermal Drug Delivery
Systems
 Membrane permeation-controlled system

Transderm – Scop (scopolamine; Ciba-Geigy)
 Adhesive dispersion-type system
Deponit (nithroglycerin; Wyeth)
 Matrix diffusion-controlled system
Nitrodur (nitroglycerin; Key)
 Microresevoir dissolution-controlled system
 Nitrodisc (Nitroglycerin; Searle)

Transdermal Device
Monolithic Membrane
Transdermal Device
Transdermal device for the delivery of scopolamine

Nasal and Pulmonary Drug
Delivery Systems
 Dry Powder Inhalations

 Aerosols
 Nasal Gels
 Nasal Sprays
 Insuffulations

Buccal Delivery
Delivery protein and peptide like drugs
Examples: Insulin, Oxytocin, Vasopressin

analogues, Buserelin, Calcitonin, etc which
cannot be given orally

Occular Drug Delivery
Systems
 Liposomes and Niosomes as carriers for

antibiotics and protein and peptides.
 Biodegradable matrix drug delivery to the
anterior segment. Polymeric dispersion
to prolong the delivery of Pilocarpine.
 Microemulsions, Self Emulsifying Drug
Delivery Systems

Occular Delivery Systems
Ocusert intraocular device for release of pilocarpine

Dental Systems
 Local administration of drugs to

periodontal pocket using biodegradable
polymers
 We are working on delivery of drugs to
periodontal pocket using biodegradable
in situ gels and matrix implants

Administration of Implant
to Periodontal Pocket

Administration of In situ gel
to Periodontal Pocket

Current and Future Trends in
Polymer Drug Delivery Systems
 Hydrogels
 Ringcap Technology
 Pulsincap Technology
 Novel Drug Delivery for Insulin
• Oral Insulin
• Molecular Gates
Hydrogels
• Hydrogels consist of polymers that swell without dissolving

in an aqueous environment (water or other biological fluid)
• At equilibrium, the gels comprise 60-90% fluid and only 10-
30% polymer
• Factors that affect release include pH, ionic strength, and
temperature
• Polymers commonly used in Hydrogels include
• Poly-(N-isopropylacrylamide)
• Poly(methacrylic acid)
• Polyethylene Glycol

Ringcap Technology
•Based on a tablet (usually film coated)

•Tablet is partially coated with a series of
“rings”
•Rings can be made of any insoluble
polymer that does not erode or degrade
during the dispensing period
•The number of rings, the position of the
rings, and the thickness of rings control the
rate of release of drug in the final dosage
form

Pulsincap
•Water insoluble capsule body and a water

soluble cap
•Capsule body contains drug and hydrogel
polymer capable of rapidly expelling the
drug at the predetermined time
•As the soluble cap erodes, the hydrogel
swells and pushes out the drug
•The hydration rate depends on the hydrogel
plug, the length of the plug and the fit ratio
(plug diameter to body diameter)

Oral Protein Delivery
 Nobex Corp. has designed a polymer that binds to

specific sites on drug structure to form drug
polymer conjugates and allows for oral delivery.
 Benefits include increased stability in the body,
ability to retain normal biological actions,
improved efficacy and safety, and increased
patient compliance
 This technology is being used to develop many
new products, one of which is oral insulin.

Synthesis of the Drug-
Polymer Molecule
The polymer blocks enzymes from attacking the protein

Molecular Gates
• A new gel has been developed

that is used to make a
“molecular gate”
• The gel expands at high pH
and shrinks at low pH.
• The gel contains two polymers
– Polymethacrylic acid
– Polyethylene glycol

Molecular Gates
 Adding the enzyme glucose oxidase causes the

gel to respond to changes in glucose levels
because the glucose and enzyme chemically
react to produce an acid.
 The gates would shrink or open at low pH to
release insulin
 As the glucose levels drop, the pH rises causing
the gates to expand and block the release of
insulin

Questions?

Thank You
E-mail: bknanjwade@yahoo.co.in
Cell No: 0091 9742431000

Controlled Drug Delivery System: Dr. Basavaraj K. Nanjwade

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Controlled Drug Delivery System

Dr. Basavaraj K. Nanjwade

09/08/2010 KLE COP, NIpani 2

 Release can be:

09/08/2010 KLE COP, NIpani 3

09/08/2010 KLE COP, NIpani 4

09/08/2010 KLE COP, NIpani 5

 With traditional administration, the drug active

 With controlled administration, the blood levels

09/08/2010 KLE COP, NIpani 6

 Controlled drug delivery occurs when a

09/08/2010 KLE COP, NIpani 7

 Eliminate over or underdosing

09/08/2010 KLE COP, NIpani 8

 Biopharmaceutic Characteristics of the Drug

 Pharmacodynamic Characteristics of the Drug

09/08/2010 KLE COP, NIpani 9

Depending on the formulation and the application,

09/08/2010 KLE COP, NIpani 10

• Lupron Depot - 1 month

09/08/2010 KLE COP, NIpani 11

These are some of the first materials selected for

09/08/2010 KLE COP, NIpani 12

These polymers became usable in controlled

• Poly 2-hydroxy ethyl methacrylate

09/08/2010 KLE COP, NIpani 13

09/08/2010 KLE COP, NIpani 15

09/08/2010 KLE COP, NIpani 16

09/08/2010 KLE COP, NIpani 17

09/08/2010 KLE COP, NIpani 18

 consists of drug dispersed homogeneously

09/08/2010 KLE COP, NIpani 19

09/08/2010 KLE COP, NIpani 20

09/08/2010 KLE COP, NIpani 22

 alternating layers of rate-controlling coats

09/08/2010 KLE COP, NIpani 23

B: Beads containing drug

09/08/2010 KLE COP, NIpani 24

Product Active Ingred Manufacturer

Contact PPA, others SKB

Diamox Sequels Acetazolamide Lederle(WA)

Chlor-Trimeton Chlorphen. Schering

09/08/2010 KLE COP, NIpani 25

09/08/2010 KLE COP, NIpani 26

 Strictly speaking, therapeutic systems will never be dependent

09/08/2010 KLE COP, NIpani 27

Drug is dispersed in the

09/08/2010 KLE COP, NIpani 28

09/08/2010 KLE COP, NIpani 29

These polymers are designed to degrade

09/08/2010 KLE COP, NIpani 30

These materials degrade within the body as a result

 Bulk hydrolysis - the polymer degrades in a fairly uniform

 Surface Eroding - degradation occurs only at the surface of

09/08/2010 KLE COP, NIpani 31

Drug delivery from

09/08/2010 KLE COP, NIpani 32

Drug delivery from

09/08/2010 KLE COP, NIpani 33

• Alza - DUROS, OROS

09/08/2010 KLE COP, NIpani 34

09/08/2010 KLE COP, NIpani 35