Transcript Controlled Drug Delivery

Controlled Drug Delivery System
Dr. Basavaraj K. Nanjwade
KLE University’s College of Pharmacy
BELGAUM- 590010, India
E-mail: [email protected]
Cell No: 0091 9742431000
“Ideal” Drug Delivery
System
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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
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Modified Drug Release
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Release can be:
• instantaneous (delayed-release)
• zero-order process (sustained release mostly non-oral)
• first-order process (oral extended
release)
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Terminology
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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
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Traditional vs. Controlled
Release Drug Dosing
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Traditional vs. Controlled
Release
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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
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Controlled Drug Delivery
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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
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Advantages of
Controlled Drug Delivery
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Eliminate over or underdosing
Maintain drug levels in desired
range
Need for less dosing
Increased patient compliance
Prevention of side effects
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Design of Controlled
Drug Delivery
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Biopharmaceutic Characteristics of the Drug
Molecular weight, Aqueous solubility, Partition coefficient,
Drug Pka and Ionization, Route of administration, Drug
stability etc
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Pharmacokinetic Characteristics of the Drug
Absorption rate, Elimination Half-Life, Rate of metabolism
etc.
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Pharmacodynamic Characteristics of the Drug
Therapeutic Range, Therapeutic index, Plasma concentration
response relatioship
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Controlled Drug Delivery
Depending on the formulation and the application,
the time of release can be quite varied
• Procardia XL - 24 hours
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Controlled Drug Delivery
• Lupron Depot - 1 month
• Norplant - 5 years
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Polymers for Controlled
Release
These are some of the first materials selected for
delivery systems bases on their intended nonbiological 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
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Current Polymers used in
Controlled Drug Delivery
These polymers became usable in controlled
delivery due to their inert physical characteristics
and being free of leachable impurities
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Poly 2-hydroxy ethyl methacrylate
Poly N-vinyl pyrrolidone
Polyvinyl alcohol
Polyacrylic acid
Polyethylene glycol
Polymethacrylic acid
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Oral Dosage Form
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Biological Factors
• Half-life
• Absorption
• active vs passive
• GI transit time
• floating systems
• bioadhesives
• penetration enhancers
• Metabolism
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Oral Dosage Form
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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
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Diffusion-Controlled
Systems
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Reservoir Devices
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Characteristics of a Reservoir
Diffusional Systems
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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
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Reservoir Diffusional
Products
PRODUCT
MANUFACTURER
Nico-400
Jones
Nitro-Bid
Marion
Nitrospan
Rorer
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Matrix Devices
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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.
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Matrix Diffusional System
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Characteristics of Matrix
Diffusion Systems
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Advantages
• easier to produce than reservoir
devices
• can deliver high molecular-weight
compounds
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Disadvantages
• cannot obtain zero-order release
• removal of remaining matrix is
necessary for implanted systems
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Matrix Diffusional
Products
Product
Manufacturer
Procan SR
Parke-Davis
Desoxyn-Gradumet
Abbott
Choledyl SA
Parke-Davis
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Dissolution-Controlled
Systems
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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
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Types of Dissolution
Controlled Systems
Two types of dissolutioncontrolled, 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
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Encapsulated
Dissolution Products
Product
Active Ingred Manufacturer
Ornade Spansules PPA, chlorphen. SKB
Contact
PPA, others
SKB
Diamox Sequels Acetazolamide
Lederle(WA)
Chlor-Trimeton
Repetabs
Schering
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Chlorphen.
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Matrix Dissolution
Products
Product
Active Ingred. Manufacturer
Dimetapp
Extentabs
Donnantal
Extentabs
Quinidex
Extentabs
Tenuate Dospan
Bromphen.
Robins
.....
Robins
Quinidine
Robins
Diethylprop.
Merrel
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Bioerodible and Combination
Diffusion and Dissolution System
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Strictly speaking, therapeutic systems will never be
dependent on dissolution only or diffusion only.
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Bioerodibile devices, however, constitute a group of systems
for which mathematical descriptions of release is complex.
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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.
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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
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Characteristics of
Bioerodible Matrix Systems
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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
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Bioerodible and Biodegradable
Controlled Release Polymers
These polymers are designed to degrade
within the body
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Polylactides (PLA)
Polyglycolides (PGA)
Polylactide-co-glycolides (PLGA)
Polyanhydrides
Polyorthoesters
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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
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Bulk hydrolysis - the polymer degrades in a fairly
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Surface Eroding - degradation occurs only at the
uniform manner throughout the matrix
surface of the polymer, resulting in a release rate that
is proportional to the surface area of the drug delivery
system
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Biodegradable Polymers
Drug delivery from
(a) bulk-eroding and
(b) surface-eroding
biodegradable systems.
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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.
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Major Companies Involved in
Polymeric Delivery Technology
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Alza - DUROS, OROS
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Alkermes Inc - Ring Caps
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Nobex Corp. - Drug/Polymer
Conjugates
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Elan - MODAS, PRODAS
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Andrx - SCOT, DPHS
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Osmotically Controlled
Systems
• osmotic
pressure provides the driving force to
generate controlled release of drug.
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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
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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
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Types of Osmotically
Controlled Systems
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Immediate Release Oxybutynin
V/s Controlled Release Ditropan XL
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Characteristics of Osmotically
Controlled Devices
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Advantages
• Zero-order release is obtainable
• reformulation is not required for different drugs
• release of drug is independent of environment of
the system
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Disadvantages
• systems can be very expensive
• quality control is more extensive
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Examples of Osmotic
Pump Systems
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Acutrim
Appetite suppressant
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Concerta
ADHD
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Procardia
Hypertension/angina
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Volmax
Bronchiodilator
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Ditropan
Overactive bladder
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Hydrodynamic Pressure
Controlled Systems
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Hydrodynamic pressure generated by swelling of a hydrophilic
gum
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The device comprises of a rigid, shape retaining housing
enclosing a collapsible, impermeable containing liquid drug
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The gun imbibes water in GIT through an opening at the lower
side of external housing and swells creating an hydrodynamic
pressure
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The pressure thus created squeeze the collapsible drug
reservoir to release the medicament through the delivery orifice
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Delayed Transit Release
Systems
• Altered Density Systems
High Density Pellets
Low Density Pellets
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Mucoadhesive Systems
Cross linked Polyacrylic acid tablet
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Intestinal Release Systems
Peyer’s patches – Proteins, Peptides, Antigens
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Colonic Release Systems
pH sensitive bioerodiable polymer polymethacrylates
Divinylbenzene cross linked polymers – azoreductase
of colonic bacteria
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Ion-Exchange Systems
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Ion-exchange systems generally use resins
composed of water soluble cross-linked polymers
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These polymers contain salt forming functional
groups in repeating position on the polymer chain
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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
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Different Novel Drug Delivery
Systems
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Microspheres, Liposomes, Niosomes
Implants
Pharmacosomes
Nanoparticles
Polymeric Films
Local drug delivery systems, etc
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Classes of Drugs for Novel
Drug Delivery
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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
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Routes of Administration
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Peroral Route
Parenteral Route
Subdermal implants
Buccal Administration
Occular Delivery
Transdermal delivery
Pulmonary Drug Delivery
Nasal delivery
Colon drug delivery
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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
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Infusaid Model 400
Implantable Pump
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Bone Implants
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Administration of Implant to
Rabbit Femur
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Transdermal Drug Delivery
Systems
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Membrane permeation-controlled system
Transderm – Scop (scopolamine; Ciba-Geigy)
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Adhesive dispersion-type system
Deponit (nithroglycerin; Wyeth)
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Matrix diffusion-controlled system
Nitrodur (nitroglycerin; Key)
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Microresevoir dissolution-controlled system
 Nitrodisc (Nitroglycerin; Searle)
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Transdermal Device
Monolithic
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Membrane
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Transdermal Device
Transdermal device for the delivery of scopolamine
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Nasal and Pulmonary Drug
Delivery Systems
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Dry Powder Inhalations
Aerosols
Nasal Gels
Nasal Sprays
Insuffulations
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Buccal Delivery
Delivery protein and peptide like drugs
Examples:
Insulin,
Oxytocin,
Vasopressin
analogues, Buserelin, Calcitonin, etc which
cannot be given orally
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Occular Drug Delivery
Systems
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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
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Occular Delivery Systems
Ocusert intraocular device for release of pilocarpine
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Dental Systems
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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
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Administration of Implant
to Periodontal Pocket
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Administration of In situ gel
to Periodontal Pocket
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Current and Future Trends in
Polymer Drug Delivery Systems
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Hydrogels
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Ringcap Technology
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Pulsincap Technology
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Novel Drug Delivery for Insulin
• Oral Insulin
• Molecular Gates
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Hydrogels
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Hydrogels consist of polymers that swell without dissolving
in an aqueous environment (water or other biological fluid)
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At equilibrium, the gels comprise 60-90% fluid and only 1030% polymer
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Factors that affect release include pH, ionic strength, and
temperature
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Polymers commonly used in Hydrogels include
• Poly-(N-isopropylacrylamide)
• Poly(methacrylic acid)
• Polyethylene Glycol
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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
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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)
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Oral Protein Delivery
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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.
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Synthesis of the DrugPolymer Molecule
The polymer blocks enzymes from attacking the protein
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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
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Molecular Gates
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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
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Questions?
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Thank You
E-mail: [email protected]
Cell No: 0091 9742431000
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