1 3-drug delivery systems

DRUG DELIVERY SYSTEMS
Dr. L.T.M. Muungo, PhD

Conventional Drug Delivery
Systems
• tablets, capsules, pills, suppositories,
creams, ointments, liquids, aerosols,
and injectables

What is controlled drug delivery
???
When a carrier is combined with the
drug
or any other active agent in such a way
that the active agent is released from
the carrier in a pre-designed manner .

New Techniques for Drug
Delivery
• control the rate of drug delivery,
sustaining the duration of therapeutic
activity
• target the delivery of drug to the
desired tissue or "site“
• respond to changes in the
environment

What is the need?
• to achieve more effective therapies
while eliminating the potential for both
under- and overdosing.
• maintenance of drug levels within a
desired range.
• the need for fewer administrations.

• increased patient compliance.
• Targeted drug delivery, in which a
particular formulation can be directed to
the specific cell, tissue, or site.

Drug levels with traditional dosing
and with controlled delivery dosing

Potential drawbacks
• the possible toxicity or non-
biocompatibility of the materials used,
• undesirable by-products of
degradation,
• any surgery required to implant or
remove the system,

• the chance of patient discomfort from
the delivery device.
• the higher cost of controlled-release
systems compared with traditional
pharmaceutical formulations.

The ideal drug delivery system
• inert
• biocompatible
• mechanically strong
• comfortable for the
patient
• capable of
achieving high drug
loading
• safe from accidental
release
• simple to
administer and
remove
• and easy to
sterilize.

CONTROLLED-RELEASE
MECHANISMS
• diffusion,
• degradation,
• swelling followed by diffusion .

Diffusion
• Matrix drug delivery system
• Reservoir delivery system

Examples
• nitroglycerine releasing transdermal
for angina.
• naltrexone in biodegradable polymer
pellets for opiate abuse rehab.

Examples
• pilocarpine-releasing ocular insert for
4-day continuous glaucoma treatment
• scopalamine-releasing transdermal for
motion sickness
• nitroglycerin-releasing transdermal
for angina

Swelling controlled systems
• Swelling-controlled release systems are
initially dry and, when placed in the
body, will absorb water or other body
fluids and swell. The swelling increases
the aqueous solvent content within the
formulation as well as the polymer
mesh size, enabling the drug to diffuse
through the swollen network into the
external environment.

BIODEGRADABLE SYSTEMS
• 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.

FUTURE DIRECTIONS IN
CONTROLLED DRUG
DELIVERY
• The most exciting opportunities in controlled
drug delivery lie in the arena of
responsive delivery systems, with
which it will be possible to deliver drugs
through implantable devices in response to a
measured blood level or to deliver a drug
precisely to a targeted site.

Environment responsive systems
PH
Ionic strength
Chemical species
Enzyme-substrate
Magnetic particles
Thermal
Electrical
Ultrasound
irradiation

DRUG DELIVERY AND THE
TREATMENT OF DIABETES
An optimal delivery system would be
one that could deliver insulin upon
detection of glucose in the bloodstream.

BIOMATERIALS FOR
DELIVERY SYSTEMS
• Poly(urethanes) for elasticity.
• Poly(siloxanes) or silicones for
insulating ability.
• Poly(methyl methacrylate) for physical
strength and transparency.
• Poly(vinyl alcohol) for hydrophilicity and
strength.
• Poly(ethylene) for toughness and lack
of swelling.

• Polylactides (PLA).
• Polyglycolides (PGA).
• Poly(lactide-co-glycolides) (PLGA).
• Polyanhydrides.
• Polyorthoesters.

Drug Delivery Carriers
• Micelles
• Liquid crystals
• Hydrogels
• Liposomes
• Nanoparticles

Micelles
• formed by self-assembly of amphiphilic block
copolymers (5-50 nm) in aqueous solutions.
• drugs can be physically entrapped in the core of the micelles,
while the hydrophilic blocks can form hydrogen bonds with the
aqueous surroundings forming a tight shell around the micellar
core.
• As a result, the contents of the hydrophobic core are effectively
protected against hydrolysis and enzymatic degradation.
• In addition, may prevent recognition by the reticulo-endothelial
system and therefore preliminary elimination of the micelles
from the bloodstream.

• A final beneficial feature of amphiphilic block
copolymers is the fact that their chemical
composition, total molecular weight and block
length ratios can be easily changed, which
allows control of the size and morphology of
the micelles.
• Substitution of block copolymer micelles with
specific ligands is a very promising strategy to
a broader range of sites of activity with a
much higher selectivity.

Liposomes
• are vesicles that consist of one, few or many
phospholipid bilayers.
• The polar character of their core enables polar drug
molecules to be encapsulated.
• Channel proteins can be incorporated without loss of
their activity within the hydrophobic domain of
vesicle membranes, acting as a size-selective filter,
only allowing passive diffusion of small solutes such
as ions, nutrients and antibiotics.

• Thus, drugs are effectively protected
from premature degradation by
proteolytic enzymes.
• The drug molecule, however, is able
to diffuse through the channel, driven
by the concentration difference
between the interior and the exterior of
the nanocage.

Liquid crystals
• Combine the properties of both liquid
and solid states.
• They can form different geometries
with alternative polar and non-polar
layers (i.e., lamellar phase), where
aqueous drug solutions can be
included.

Nanoparticles
• Nanoparticles (size 10-200 nm) are in the
solid state and are either amorphous or
crystalline. They are able to adsorb and/or
encapsulate a drug, thus protecting it against
chemical/enzymatic degradation.
• In recent years, biodegradable nanoparticles
have attracted considerable attention as
potential drug delivery devices.

Hydrogels
• Are three-dimensional, hydrophilic, polymeric
networks capable of imbibing large amounts
of water or biological fluids.
• The networks are composed of
homopolymers or copolymers, and are
insoluble due to the presence of crosslinks.

TRANSDERMAL DRUG
DELIVERY SYSTEMS
• Transdermal drug delivery systems
are topicaly administered
medicaments in the form of
patches that deliver drugs for
systemic effects at a
predetermined and controlled rate

Advantages over conventional
dosage forms
• Avoidance of the 'first pass effect‘
•
A stable and controlled blood level
• Comparable characteristics with intravenous
infusion
• Termination of further administration,if
necessary

• Long-term duration (ranging from a few
hours to one week).
•
No interference with gastric and intestinal
fluids.
• Administration of drugs with:
- A very short half-life
- Narrow therapeutic window
- Poor oral absorption

Molecules Formulated as
TDDS
• Scopolamine
• Nitroglycerin
• Estradiol
• Progestins
• Nicotine
• Lidocaine
• Clonidine
• Testosterone
• Fentanyl
• Diclofenac
• Ketoprofen

Factors determining weather a
moleclule can be incorporated in a
TDDS
• dose of the actives
• the molecular weight
• crystalline state
• melting point
• skin reactions (mainly irritation and
sensitisation

KINETICS OF TRANSDERMAL
PERMEATION
. Transdermal permeation of a drug
involves the following steps:
1. Sorption by stratum corneum.
2. Penetration of drug through viable
epidermis.
3. Uptake of the drug by the capillary
network in the dermal papillary layer

Basic Components of
Transdermal Drug Delivery
Systems
1. Polymer matrix or matrices.
2. The drug
3. Permeation enhancers
4. Other excipients

Polymer Matrix
The Polymer controls the release of the drug from the device.
• Natural Polymers:
Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins,
Gums and their derivatives, Natural rubber, Starch etc.
• Synthetic Elastomers:
Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber,
Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber,
Neoprene etc.
• Synthetic Polymers:
Polyvinyl alcohol, Polyvinyl chloride, Polyethylene,
Polypropylene, Polyacrylate, Polyamide, Polyurea,
Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.

Drug
• For successfully developing a transdermal drug
delivery system, the drug should be chosen with
great care. The following are some of the desirable
properties of a drug for transdermal delivery.
• Physicochemical properties
1. The drug should have a molecular weight less
than approximately 1000 daltons.
2. The drug should have affinity for both – lipophilic
and hydrophilic phases. Extreme partitioning
characteristics are not conducive to successful drug
delivery via the skin.
3. The drug should have low melting point.

Permeation Enhancers
These are compounds which promote
skin permeability by altering the skin as
a barrier to the flux of a desired
penetrant.

a) Solvents
These compounds increase penetration
possibly by swallowing the polar
pathway and/or by fluidizing lipids.
Examples include water alcohols –
methanol and ethanol; alkyl methyl
sulfoxides – dimethyl sulfoxide, alkyl
homologs of methyl sulfoxide dimethyl
acetamide and dimethyl formamide ;
pyrrolidones – 2 pyrrolidone,

b) Surfactants
These compounds are proposed to enhance polar
pathway transport, especially of hydrophilic
drugs.The ability of a surfactant to alter penetration
is a function of the polar head group and the
hydrocarbon chain length.
• Anionic Surfactants: e.g. Dioctyl sulphosuccinate,
Sodium lauryl sulphate, Decodecylmethyl sulphoxide
etc.
• Nonionic Surfactants: e.g. Pluronic F127, Pluronic
F68, etc.
• Bile Salts: e.g. Sodium ms taurocholate, Sodium
deoxycholate, Sodium tauroglycocholate.

c) Miscellaneous chemicals
These include urea, a hydrating and
keratolytic agent.

Other Excipients
a) Adhesives:
• Should adhere to the skin aggressively, should be
easily removed.
• Should not leave an unwashable residue on the skin.
• Should not irritate or sensitize the skin.
• Permeation of drug should not be affected.

b) Backing membrane:
Backing membranes are flexible and
they provide a good bond to the drug
reservoir, prevent drug from leaving the
dosage form through the top.

Desirable features for
transdermal patches
• Composition relatively invariant in use.
• System size reasonable.
• Defined site for application.
• Application technique highly
reproducible.
• Delivery is (typically) zero order.
• Delivery is efficient.

TYPES OF TRANSDERMAL
PATCHES
Three Major Transdermal Systems

PULMONARY DRUG DELIVERY
• Growing attention has been given to the
potential of a pulmonary route as a non-
invasive administration for systemic delivery
of therapeutic agents (mainly peptides and
proteins) due to the fact that the lungs could
provide a large absorptive surface area (up to
100 m2 ) but extremely thin (0.1 µm – 0.2
µm) absorptive mucosal membrane and good
blood supply

• Despites the many challenges faced by
pulmonary drug delivery system,
several peptide and protein drugs are
currently investigated for potential
systemic absorption through
pulmonary system

• Insulin
• Calcitonin
• LHRH analogs
• Granulocyte colony-stimulating factor
(G-CSF),
• Growth hormone

The drugs can be administered by
pulmonary route utilizing two
techniques:
• Aerosol inhalation
• Intratracheal instillation

Aerosols
There are three commonly used clinical
aerosols:
• jet or ultrasonic nebulizers
• metered–dose inhaler (MDI)
• dry-powder inhaler (DPI)
The metered–dose inhalers are most
frequently used aerosol delivery
system.

• All aerosols used to have CFC
propellants
• But since the mid- ninties, CFCs have
been replaced by hydrofluroalkanes
(HFAs)

The future of pulmonary drug
delivery / carrier systems
Pulmonary bioavailability of drugs
could be improved by including various
permeation enhancers such as
• surfactants,
• fatty acids,
• saccharides
• chelating agents
• enzyme inhibitors such as protease
inhibitors.

• Some reports suggest that pulmonary
absorption of insulin was significantly enhanced
in the presence of several adjuvants such as
glycocholate, surfactin, span 85, and others.
• Calcitonin was delivered with various fatty acids,
surfactants, and protease inhibitors and effect of
these were studied for enhancement of
absorption in the lungs to evaluate the
pharmacological response and plasma calcium
reduction

• Insulin liposomes are one of the recent
approaches in the controlled release
aerosol preparation. Intratracheal
delivery of insulin liposomes have
significantly enhanced the desired
hypoglycemic effect

In another method, pulmonary
absorption properties were modified for
protein/ peptide drugs in conjugation
with polyethylene glycol (PEGylation) to
enhance the absorption of the protein
drug.

LATEST DEVELOPMENTS
• Nektar therapeutics in conjunction with
Pfizer began dosing diabetic patients for
the phase III clinical trial for inhaleable
insulin Exubera.

OCULAR ROUTE AND DRUG
DELIVERY SYSTEMS
• A large proportion of the topically applied
pharmaceutical system is immediately
diluted in the tear film and excess fluid
spills over the lid margin and the remainder
is rapidly drained into the nasolacrymal
duct
• These processes lead to a typical corneal
contact time of about 1 to 2 minutes in
humans, and an ocular bioavailability that is
commonly less than 10%.

Required charcteristics for optimal
drug delivery
• A good corneal penetration
• A prolonged contact time with the
corneal epithelium
• A simplicity of instillation for the patient
• A non-irritative and comfortable form.

Various ocular systems
• Hydrogels
• Bioadhesive dosage forms
• Liposomes and nanoparticles.

• Bioadhesive systems can be either polymeric
solutions or microparticle suspensions. Such
polymers have demonstrated increased ocular
bioavailability by increasing the drug
residence time in the pre-corneal area .
• Encapsulation of drugs in liposomes and
nanoparticles was correlated to an increase of
the drug concentration in the ocular tissues.

ORAL DRUG DELIVERY SYSTEMS
• Bio-avaiability can be enhanced by
increasing gastric emptying time with
the help of flotation devices.
• Colon targeted delivery.

Flotation devices
Floating drug delivery systems are
classified into:
• effervescent
• non-effervescent systems.

Effervescent Floating Dosage
Forms
• These are matrix types of systems
prepared with the help of swellable
polymers such as methylcellulose and
chitosan and various effervescent
compounds, eg, sodium bicarbonate,
tartaric acid, and citric acid.

• They are formulated in such a way that
when in contact with the acidic gastric
contents, CO2 is liberated and gets
entrapped in swollen hydrocolloids,
which provides buoyancy to the dosage
forms.

Non-Effervescent Floating Dosage
Forms
• Non-effervescent floating dosage forms use a
gel forming or swellable cellulose type of
hydrocolloids, polysaccharides, and matrix-
forming polymers like polycarbonate,
polyacrylate, polymethacrylate, and
polystyrene.
• The formulation method includes a simple
approach of thoroughly mixing the drug and
the gel-forming hydrocolloid.

After oral administration this dosage
form swells in contact with gastric fluids
and attains a bulk density of < 1. The
air entrapped within the swollen matrix
imparts buoyancy to the dosage form.
The so formed swollen gel-like structure
acts as a reservoir and allows sustained
release of drug through the gelatinous
mass.

Marketed Preparations of Floating
Drug Delivery Systems
• Levodopa
• Benserzide
• Diazepam
• Aluminum magnesium antacid
• Alginic acid and sodium bicarbonate

Colon Targeted Delivery
• Colonic drug delivery has gained
increased importance not just for the
delivery of the drugs for the treatment
of local diseases associated with the
colon but also for its potential for the
delivery of proteins and therapeutic
peptides.

• To achieve successful colonic delivery, a
drug needs to be protected from
absorption and /or the environment of
the upper gastrointestinal tract (GIT)
and then be abruptly released into the
proximal colon, which is considered the
optimum site for colon-targeted delivery
of drugs.

Various pharmaceutical
approaches to colon targeted drug
delivery systems
• Covalent linkage of
the drug with a
carrier
• Approaches to deliver
the intact molecule to
the colon

Covalent linkage of the drug
with a carrier
• Azo bond conjugates
• Glycoside conjugates
• Glucuronide conjugates
• Cyclodextrin conjugates
• Dextran conjugates
• Amino-acid conjugates

Approaches to deliver the
intact molecule to the colon
• Coating with polymers
• Coating with pH-sensitive
polymers
• Embedding in matrices
• Embedding in biodegradable
matrices and hydrogels
• Coating with microparticles
• Coating with biodegradable
polymers
• Embedding in pH-sensitive
matrices
• Timed release systems
• Redox-sensitive polymers
• Bioadhesive systems
• Osmotic controlled drug
delivery

Refferences(Contd.)
• Vert M, Li S, and Garreau H, "More About the Degradation of
LA/GA-derived Matrices in Aqueous Media," J Controlled
Release, 16:15–26, 1991.
• Cleary GW, "Transdermal Drug Delivery," Cosmetics and
Toiletries, 106:97–107, 1991.
• Cleary GW, "Transdermal Delivery Systems: A Medical
Rationale," in Topical Drug Bioavailability, Bioequivalence, and
Penetration, Shah VP, and Maibach HI (eds), New York, Plenum,
pp 17–68, 1993.
• Kim SW, "Temperature Sensitive Polymers for Delivery of
Macromolecular Drugs," in Advanced Biomaterials in Biomedical
Engineering and Drug Delivery Systems, Ogata N, Kim SW,
Feijen J, et al. (eds), Tokyo, Springer, pp 126–133, 1996.
• Heller J, "Controlled Drug Release from Poly(ortho esters)—A
Surface Eroding Polymer," J Controlled Release, 2:167–177,
1985.

Refferences(Contd.)
• Domb AJ (ed), Polymeric Site-Specific Pharmacotherapy,
Chichester, UK, Wiley, 1994.
• Chien, YW, Novel drug delivery systems, Drugs and the
Pharmaceutical Sciences, Vol.50, Marcel Dekker, New York,
NY;1992;797
• Roberts MS, Targeted drug delivery to the skin and deeper
tissues: role of physiology, solute structure and disease.Clin Exp
Pharmacol Physiol 1997 Nov;24(11):874-9.
• Aulton.M.E, Pharmaceutics; The science of dosage form design,
second edition, Churchill Livingston, Harcourt publishers-2002.
• Ansel.H.C, Loyd.A.V, Popovich.N.G, Pharmaceutical dosage
forms and drug delivery systems, Seventh edition, Lippincott
Williams and Willkins publication.

Refferences(Contd.)
• Brahmankar.D.M, Jaiswal.S.B, Biopharmaceutics and
pharmacokinetics A Teatise. Vallabh Prakashan, Delhi1995,335-
371.
• Banker, G. S and Rhodes, C. T Modern pharmaceutics, third
edition, New York, Marcel Dekker, inc,. 1990.
• Jain.N.K, Controlled and novel drug delivery ,first edition, CBS
publishers and distributors, New Delhi.1997.
• Mathiowitz.Z.E, Chickering.D.E, Lehr.C.M, Bioadhesive drug
delivery systems; fundamentals,novel approaches and
development, Marcel Dekker, inc New York . Basel
• www.Controlled release drug delivery systems.com
• 3M World Wide, 3M Drug delivery system, Transdermal patches,
http://www.3mworldwide.com/
• Ryan D. Gordon, and Tim A. Peterson, transdermal drug
delivery , drug delivery technology,
http://www.drugdeliverytechnology.com/
• www.biomed.brown.edu/Courses/BI108

ROUTES
• ORAL
• PARENTERAL
• SUBLINGUAL
• BUCCAL
• RECTAL
• VAGINAL
• OCULAR
• OTIC
• NASAL
• INHALATIONAL
• CUTANEOUS
• TRANS-DERMAL

ORAL
• Most convenient
• Safest, least expensive
• Limitations:
1. Absorption in mouth & stomach --
small intestines
2. Metabolism in intestinal wall & liver=
decreased drug amount

ORAL
• Limitations:
3. Food & other drugs = affect amount &
rate of drug absorbed
4. Irritation of digestive tract
5. Poor/erratic absorption = destroyed
by acid or enzymes

Oral route exclusion criteria
• Cannot take anything per oral admin.
• Drug must be administered rapidly;
precisely; in very high dose
• Expected poor or erratic digestive tract
absorption

Parenteral
• Methods: subcutaneous, intramuscular,
intravenous & intrathecal
• Drug may be prepared to prolong
absorption from site

Subcutaneous
• Inserted into fatty tissues just beneath
skin; drug moves into capillaries into
bloodstream or lymphatics
• Used for many protein drugs (digested
through oral route)

Intramuscular
• Preferred for large drug volumes
• Longer needle (muscles are below skin
& fatty tissues)
• Upper arm, thigh or buttocks
• Absorption ~muscle blood supply
Physical activity increases blood supply

Intravenous
• Needle directly inserted into a vein
• Single dose or continuous infusion
1. Gravity (collapsible plastic bag)
2. Infusion pump (catheter)
• Delivers a precise dose quickly;
well-controlled
• Used for irritating solutions
• May be difficult to administer (obese)

Intravenous
• Immediate delivery of drug into the
bloodstream
• Effect is more quick
• Needs monitoring: for drug effects or
adverse reactions
• Tendency for shorter duration

Intrathecal
• Inserted between two vertebrae, into
the space around the spinal cord
• Injected into spinal canal
• Produces rapid or local effects on
brain, spinal cord or meninges

Sublingual
• Placed under the tongue
• Direct absorption into small blood
vessels
• Rapid absorption without initial
hepatic first-pass effect
• Some drugs absorbed incompletely or
erratically

Buccal
• Placed in the buccal pouch
• Direct absorption into small blood
vessels of buccal mucosa
• Rapid absorption without initial
hepatic first-pass effect
• Some drugs absorbed incompletely or
erratically

Rectal
• As a suppository: mixed with a waxy
substance that liquefies/dissolves after
rectal insertion
• Rectal wall is thin with rich blood
supply
• For patients : nauseous, cannot
swallow, have eating restrictions

Vaginal
• As a solution, tablet, cream, gel, or
suppository
• Slow absorption through vaginal wall
eg. (Estrogen in menopausal women {prevents
vaginal wall thinning})

Introduction
• The external eye is readily accessible for drug administration.
As a consequence of its function as the visual apparatus,
mechanisms are strongly developed for the clearance of
foreign materials from the cornea to preserve visual acuity.
This presents problems in the development of formulations
for ophthalmic therapy
• Topical administration is direct, but conventional
preparations of ophthalmic drugs, such as ointments,
suspensions, or solutions, are relatively inefficient as
therapeutic systems

Introduction
• Following administration, a large proportion of the topically
applied drug is immediately diluted in the tear film and
excess fluid spills over the lid margin and the remainder is
rapidly drained into the nasolacrimal duct
• A proportion of the drug is not available for immediate
therapeutic action since it binds to the surrounding
extraorbital tissues
• In view of these losses, frequent topical administration is
necessary to maintain adequate drug levels.

Introduction
• Systemic administration of a drug to treat ocular
disease would require a high concentrations of
circulating drug in the plasma to achieve
therapeutic quantities in the aqueous humor, with
the increased risk of side effects

Structure of eye
• The eye is composed of two
components
1. anterior segment: consists of front one-
third of eye that mainly includes pupil,
cornea, iris, ciliary body, aqueous humor,
and lens
2. posterior segment: consists of the back
two-thirds of the eye that includes vitreous
humor, retina, choroid, macula, and optic
nerve

Routes of drug administration
• Topical Administration
– Drops
– Perfusion
– Sprays
– Ointments
– Particulates
• Intraocular drug delivery
– Liposomes
– Microparticulates and nanoparticles
– Intraocular devices
– Iontophoresis

Drops
• The most common form of topical administration is the eye drop. It
is apparently easy to use, relatively inexpensive and does not
impair vision.
• The major problems with these types of formulation are their
inability to sustain high local concentrations of drug and they only
have a short contact time with the eye
• Contact time between the vehicle and the eye can be increased by
the addition of polymers such as polyvinyl alcohol and
methylcellulose
• Drainage from the cul-de-sac may also be reduced by punctual
occlusion or simple eyelid closure, which prolongs the contact time
of the drug with the external eye. This serves two purposes- first it
maximizes the contact of drug with the periocular tissues
increasing absorption through the cornea and second, the systemic
absorption is reduced.

Perfusion
• Continuous and constant perfusion of the eye with drug solutions
can be achieved by the use of ambulatory motor driven syringes
that deliver drug solutions through fine polyethylene tubing
positioned in the conjunctival sac
• The flow rate of the perfusate through a minipump can be adjusted
to produce continuous irrigation of the eye surface (3– 6 ml/min)
or slow delivery (0.2 ml/min) to avoid overflow
• This system allows the use of a lower drug concentration than used
in conventional eye-drops, yet will produce the same potency. Side
effects are reduced and constant therapeutic action is maintained
• This system is not used very often due to the inconvenience and
the cost involved, but may find application for irritant drugs or for
sight-threatening situations

Sprays
• Spray systems produce similar results to eye-drops in terms
of duration of drug action and side effects. Sprays have
several advantages over eye-drops:
1. a more uniform spread of drug can be achieved
2. precise instillation requiring less manual dexterity than for eye-
drop administration and is particularly useful for treating
patients with unsteady hand movements
3. contamination and eye injury due to eye-drop application are
avoided
4. spray delivery causes less reflex lacrimation.
5. Can be used by patients who have difficulty bending their neck
back to administer drops.
• The only disadvantage is that sprays are more expensive to
produce than eye-drops so they are not widely used

Ointments
• Ointments are not as popular as eye drops since vision is
blurred by the oil base, making ointments impractical for
daytime use
• They are usually applied for overnight use or if the eye is to
be bandaged. They are especially useful for paediatric use
since small children often wash out drugs by crying.
• Ointments are generally non-toxic and safe to use on the
exterior of the surface of the eye. However, ointment bases
such as lanolin, petrolatum and vegetable oil are toxic to the
interior of the eye, causing corneal oedema, vascularization
and scarring

Ointments
• Antibiotics such as tetracyclines are used in the form of an
ointment, producing effective antibacterial concentrations in
the anterior chamber for several hours, whereas an aqueous
solution of tetracycline is ineffective for intraocular infections.

Particulates
• Poorly soluble drugs for ophthalmic administration are
frequently formulated as micronised suspensions. Larger
particles theoretically provide prolongation of effect due to
the increased size of the reservoir; however, an increase in
particle size is associated with irritation giving rise to an
increased rate of removal, assisted by agglomeration of
particles and ejection.
• submicron or nanosphere formulations demonstrate
therapeutic advantages over aqueous solutions
• For example, pilocarpine (2% w/v) adsorbed onto a
biocompatible latex of average size 0.3 μm will maintain a
constant miosis in the rabbit for up to 10 hours compared to
4 hours with pilocarpine eye drops

Routes of drug adminstration
• Topical Administration
– Drops
– Perfusion
– Sprays
– Ointments
– Particulates
• Intraocular drug delivery
– Liposomes
– Microparticulates and nanoparticles
– Intraocular devices
– Iontophoresis

Liposomes
• Liposomal encapsulation has the potential not only to
increase the activity and prolong the residence of the drug in
the eye, but also to reduce the intraocular toxicity of certain
drugs
• For example, liposome-encapsulated amphotericin B
produces less toxicity than the commercial solubilized
amphotericin B formulation when injected intravitreally
• The main drawbacks associated with liposomes are their
short shelf life and difficulty in storage, limited drug loading
capacity and instability on sterilization and finally, transient
blurring of vision after an intravitreal injection

Microparticulates and nanoparticles
• Microspheres and nanoparticles are retained for extended
periods within the eye and can provide slow, sustained
release of drugs
• The delivery systems are especially attractive because of the
ease of manufacturing and improved stability compared to
liposomes
• The polymers used in the manufacture can be erodible, in
which case the drug release is due to the polymer
degradation, or non-erodible, where the drug is released is
by diffusion through the polymer

Intraocular devices
• The administration of medications by implants or depot devices is a
very rapidly developing technology in ocular therapeutics. These
overcome the potential hazards associated with repeated
intravitreal injection such as clouding of the vitreous humor, retinal
detachment and endophthalmitis
• Implantable devices have been developed that serve two major
purposes. First, to release of drug at zero order rates, thus
improving the predictability of drug action, and second, to release
of the drug over several months, reducing dramatically the
frequency of administration.
• Vitrasert® is a commercially available sustained release intraocular
device for ganciclovir approved for use in-patients suffering from
cytomegalovirus

Iontophoresis
• Iontophoresis (see transdermal lecture notes) facilitates drug
penetration through the intact corneal epithelium
• The solution of the drug is kept in contact with the cornea in
an eyecup bearing an electrode. A potential difference is
applied with the electrode in the cup having the same charge
as the ionized drug, so that the drug flux is into the tissue
• This method of administration is very rarely used, except
under carefully controlled conditions. Iontophoresis allows
penetration of antibiotics that are ionised and therefore do
not penetrate by other methods, for example, polymyxin B
used in the local treatment of infections

Iontophoresis
• Commonly reported toxic effects include slight retinal and
choroidal burns and retinal pigment epithelial and choroidal
necrosis, corneal epithelial oedema, persistent corneal
opacities and polymorphonuclear cell infiltration. Other
disadvantages of iontophoresis include side effects such as
itching, erythema and general irritation

Ocular
• Mixed with inactive substances to make a
liquid, gel, or ointment
• Liquid: easy, runs off quickly to be absorbed
well
• Gel/ointment: longer eye surface contact
• Solid inserts: releases drug continuously, in
small amounts: hard to put & keep in place

Nasal
• In atomized form
• Breathed in, absorbed by thin mucous
membrane lining of nasal passages
• Enters bloodstream = generally works
quickly

Inhalational
• Anesthetic gases
• Through the nose or mouth
• Few drugs: close monitoring= right
amount within a specified time
• Administer drug that act on lungs:
metered-dose, aerosolized anti-
asthma drugs

Pulmonary Drug Delivery
• Anatomy and Physiology of the
Respiratory System
• Advantages of Pulmonary Delivery
• Pulmonary Drug Delivery Devices

Anatomy and Physiology of the Respiratory
System
• The human respiratory system is divided into upper and
lower respiratory tracts
• The upper respiratory system consists of the nose,
nasal cavities, nasopharynx, and oropharynx
• The lower respiratory tract consists of the larynx,
trachea, bronchi, and alveoli, which are composed of
respiratory tissues
• The left and right lungs are unequal in size. The right
lung is composed of three lobes: the superior, middle,
and inferior lobes. The smaller left lung has two lobes

System
• The nasopharynx is a passageway from the nose to the
oral pharynx
• The larynx controls the airflow to the lungs and aids in
phonation
• The larynx leads into the cartilaginous and
fibromuscular tube, the trachea, which bifurcates into
the right and left bronchi
• The bronchi, in turn, divide into bronchioles and finally
into alveoli

System
• The respiratory tree can be differentiated into the
conducting zone and the respiratory zone.
• The conducting zone consists of the bronchi, which are
lined by ciliated cells secreting mucus and terminal
bronchioles.
• The respiratory zone is composed of respiratory
bronchioles, alveolar ducts, atria, and alveoli

System

System
• The epithelium in the conducting zone gets thinner as it
changes from pseudostratified columnar to columnar
epithelium and finally to cuboidal epithelium in the
terminal bronchioles
• The upper part of the conducting zone (from the
trachea to the bronchi) consists of ciliated and goblet
cells (which secrete mucus)
• These cells are absent in the bronchioles. Alveoli are
covered predominantly with a monolayer of squamous
epithelial cells (type I cells) overlying a thin basal
lamina

System
• Cuboidal type II cells present at the junctions of alveoli
secrete a fluid containing a surfactant
(dipalmitoylphosphatidylcholine), apoproteins, and calcium
ions
• The lungs are covered extensively by a vast network of
blood vessels, and almost all the blood in circulation flows
through the lungs. Deoxygenated blood is supplied to the
lungs by the pulmonary artery
• The pulmonary veins are similar to the arteries in
branching, and their tissue structure is similar to that of
systemic circulation. The total blood volume of the lungs
is about 450 mL, which is about 10 percent of total body
blood volume

Advantages of Pulmonary Delivery of Drugs
To Treat Respiratory Disease
• Deliver high drug concentrations directly to the disease site
• Minimizes risk of systemic side effects
• Rapid clinical response
• Bypass the barriers to therapeutic efficacy, such as poor
gastrointestinal absorption and first-pass metabolism in the
liver
• Achieve a similar or superior therapeutic effect at a fraction
of the systemic dose, (for example, oral salbutamol 2–4 mg
is therapeutically equivalent to 100–200 μg by metered dose
inhaler)

To Treat Systemic Disease
• A non-invasive, needle-free delivery system
• Suitable for a wide range of substances from small
molecules to very large proteins
• Enormous absorptive surface area (140 m2) and a
highly permeable membrane (0.2–0.7 μg thickness) in
the alveolar region
• Large molecules with very low absorption rates can be
absorbed in significant quantities; the slow mucociliary
clearance in the lung periphery results in prolonged
residency in the lung

To Treat Systemic Disease
• A less harsh, low enzymatic environment
• Avoids first-pass metabolism
• Reproducible absorption kinetics
• Pulmonary delivery is independent of dietary
complications, extracellular enzymes, and inter-patient
metabolic differences that affect gastrointestinal
absorption

Pulmonary Drug Delivery
• Anatomy and Physiology of the Respiratory System
• Advantages of Pulmonary Delivery
• Lung epithelium at different sites within the lungs
• Pulmonary absorptive surfaces
• Systemic delivery of:
– Small hydrophobic drugs
– Small hydrophilic drugs
– Macromolecules drugs

Comparison of the lung epithelium at
different sites within the lungs

Pulmonary absorptive surfaces
• The airways (the trachea, bronchi and bronchioles) are
composed of a gradually thinning columnar epithelium
populated by many mucus and ciliated cells that
collectively form the mucociliary escalator
• The airways bifurcate roughly 16–17 times before the
alveoli are reached
• Inhaled insoluble particles that deposit in the airways
are efficiently swept up and out of the lungs in moving
patches of mucus, and for those deposited in the
deepest airways this can be over a time period of about
24 hour

• The monolayer that makes up the alveolar epithelium is
completely different. The tall columnar mucus and cilia
cells are replaced primarily (>95% of surface) by the very
broad and extremely thin (<0.1 µm in places) type 1 cells
• Distributed in the corners of the alveolar sacs are also the
progenitor cells for the type 1 cells and the producers of
lung surfactant, the type 2 cells
• The air-side surface of each of the 500 million alveoli in
human lungs is routinely 'patrolled' by 12–14 alveolar
macrophages, which engulf and try to digest any insoluble
particles that deposit in the alveoli

• An excess of 90% of alveolar macrophages are located
at or near alveolar septal junctional zones
• Insoluble, non-digestible particles that deposit in the
alveoli can reside in the lungs for years, usually
sequestered within macrophages
• Molecules such as insulin are formulated either as
liquids or in highly water-soluble aerosol particles that
dissolve rapidly in the lungs and thereby largely avoid
macrophage degradation

• Protein therapeutics that are taken up by macrophages
can be rapidly destroyed in the lysosomal 'guts' of the
phagocytic cells

The effect of particle size on the deposition of aerosol
particles in the human respiratory tract following a slow
inhalation and a 5-second breath hold

Systemic delivery of small
hydrophobic molecules
• Small, mildly hydrophobic molecules can show extremely
rapid absorption kinetics from the lungs
• However, as hydrophobicity increases, molecules can
become too insoluble for rapid absorption and can persist in
the lungs for hours, days or weeks
• Typical drug molecules with log octanol–water partition
coefficients greater than 1 can be expected to be absorbed,
with absorption half-lives (the time it takes half of the
molecules deposited into the lungs to disappear from the
tissue) of approximately 1 minute or so; decreasing the log
octanol–water partition coefficient to –1 or lower can
increase the half-life to around 60 minutes

Systemic delivery of small
hydrophobic molecules
• Examples of rapidly absorbed inhaled hydrophobic drugs
include nicotine, 9-tetrahydrocannabinol (THC), morphine
and fentanyl

Inhaled morphine (dose = 8.8 mg)
compared with intravenous injection (dose
= 4 mg) in human volunteers

Systemic delivery of small hydrophilic
molecules
• In general, neutral or negatively charged hydrophilic
small molecules are absorbed rapidly and with high
bioavailabilities from the lungs
• This class of molecules has an average absorption half-
life of about 60 minutes, in contrast to some of the
lipophilic molecules that are absorbed in seconds to
minutes

Systemic delivery of macromolecules
• The use of the lungs for the delivery of peptides and
proteins, which otherwise must be injected, is one of
the most exciting new areas in pulmonary delivery
• For reasons that are not completely understood, the
lungs provide higher bioavailabilities for
macromolecules than any other non-invasive route of
delivery
• However, unlike the situation with small molecules, for
which lung metabolism is minimal, enzymatic hydrolysis
of small natural peptides can be very high unless they
are chemically engineered (blocked) to inhibit
peptidases

• Small natural peptides make poor drugs by any route of
delivery because of peptidase sensitivity, whereas
blocked peptides show high pulmonary bioavailabilities
• As molecular mass increases and peptides become
proteins with greater tertiary and quaternary structure,
peptidase hydrolysis is inhibited or even eliminated and
bioavailabilities of natural proteins can be high
• Insulin can be considered to be a large peptide (or
small protein), with enough size to avoid much of the
metabolism seen with smaller peptides

• The rate of macromolecule absorption is primarily
dictated by size — the larger the size the slower the
absorption
• Molecules such as insulin, growth hormone and many
cytokines typically peak in blood following aerosol
inhalation in 30–90 minutes, whereas smaller blocked
peptides can be absorbed faster
• After a 15-year development effort, inhaled human
insulin (IHI) applied regularly at meal time has been
approved both in the US and the European Union for
the treatment of adults with diabetes (Exubera)

• Conjugation of molecules such as interferons, follicle
stimulating hormone (FSH) and erythropoietin (EPO) to
the constant (Fc) region of antibodies has been shown to
prolong the systemic duration
• Interestingly, the optimal pulmonary site of absorption of
these conjugates seems to be the conducting airways, in
contrast to the major site for insulin, which is in the deep
lung
• The airways are enriched with antibody transcytosis
receptor mechanisms. Fc conjugates of proteins have
serum half-lives >1 day and are believed to be absorbed
with high bioavailabilities (20–50%) from the lungs

Pulmonary Drug Delivery Devices
• Dry Powder Inhalation (DPI) Devices
• The Pressurized Metered-Dose Inhalation (pMDI)
Device
• Nebulizers

Dry Powder Inhalation (DPI)
Devices• DPIs are used to treat respiratory diseases such as
asthma and COPD, systemic disorders such as diabetes,
cancer, neurological diseases (including pain), and
other pulmonary diseases such as cystic fibrosis and
pulmonary infectious diseases
• Devices requiring the patient's inspiration effort to
aerosolize the powder aliquot are called passive devices
because as they do not provide an internal energy
source
• Active devices provide different kinds of energy for
aerosolization: kinetic energy by a loaded spring and
compressed air or electric energy by a battery

Dry Powder Inhalation (DPI)
Devices• Most DPIs contain micronized drug blended with larger
carrier particles, which prevents aggregation and
promotes flow

Principle of dry powder inhaler
design

The Pressurized Metered-Dose
Inhalation (pMDI) Device• The pressurized metered-dose inhalation (pMDI) device
was introduced to deliver asthma medications in a
convenient and reliable multi-dose presentation
• The key components of the pMDI device are:container,
propellants, formulation, metering valve, and actuator
• The pMDI container must withstand high pressure
generated by the propellant. Stainless steel has been used
as a pMDI container material. Aluminum is now preferred
because, compared to glass, it is lighter, more compact,
less fragile, and light-proof

Inhalation (pMDI) Device
• Coatings on the internal container surfaces may be
useful to prevent adhesion of drug particles and
chemical degradation of drug
• Propellants in pMDIs are liquefied, compressed gases
that are in the gaseous phase at atmospheric pressure
but form liquids when compressed
• They are required to be nontoxic, nonflammable,
compatible with drugs formulated either as suspensions
or solutions, and to have appropriate boiling points and
densities

Inhalation (pMDI) Device

Nebulizers
• A nebulizer is a device used to administer medication to
patient in the form of a mist inhaled into the lungs
• It is commonly used in treating cystic fibrosis, asthma, and
other respiratory diseases
• There are two basic types of nebulizers:
– The jet nebulizer functions by the Bernoulli principle by which
compressed gas (air or oxygen) passes through a narrow orifice,
creating an area of low pressure at the outlet of the adjacent liquid
feed tube. This results in the drug solution being drawn up from
the fluid reservoir and shattering into droplets in the gas stream
– The ultrasonic nebulizer uses a piezoelectric crystal, vibrating at a
high frequency (usually 1–3 MHz), to generate a fountain of liquid
in the nebulizer chamber; the higher the frequency, the smaller the
droplets produced

Cutaneous
• Local effects
• Treat superficial skin disorders
• Drug is mixed with inactive substances:
ointment, cream, lotion, solution,
powder or gel

Transdermal
• Drug mixed with chemicals which enhance
skin penetration
• Patch: slow, continuous delivery=constant
drug blood level
• Treat superficial skin disorders
• Drug is mixed with inactive substances:
ointment, cream, lotion, solution, powder or
gel

Transdermal
• Patches may irritate skin
• Limited by relatively small dose
• or volume & how quickly drug can
penetrateskin

Transdermal drug delivery systems are
designed to support the passage of
drug substances from the surface of
the skin, through its various layers, and
into the systemic circulation,
offering a more sophisticated
and more reliable means of
administering drug through
the skin.
TRANSDERMAL DRUG DELIVERY SYSTEMS

1. Avoids gastrointestinal drug absorption
difficulties caused by gastrointestinal
pH, enzymatic activity, drug interactions
with food, drink, or other orally
administered drugs.
2. Substitutes for oral administration in
cases of vomiting and/or diarrhea.
3. Avoids first-pass effect avoiding the
drug's deactivation by digestive and
liver enzymes.
ADVANTAGES OF TRANSDERMAL DRUG DELIVERY SYSTEMS:

4. Avoids the risks of parenteral therapy.
5. Provides the capacity for multiday therapy with a single
application.
6. Provides capacity to terminate drug effect rapidly.
7. Provides ease and rapid administration of the medication
in emergencies.

Disadvantages of transdermal drug delivery systems:
1. The transdermal route of administration is unsuitable for
drugs that irritate or sensitize the skin.
2. Only relatively potent drugs are suitable for transdermal
delivery due to the natural limits of drug entry by the
skin's impermeability.
3. Technical difficulties with the adhesion of the systems to
different skin types and under various environmental
conditions.

The Skin
The skin has a wide variety of functions:
Protect the organism from water loss and
mechanical, chemical, microbial, and physical
influences.

Structure of the Skin
The skin is the largest human organ and is composed of:
 A film of emulsified material present upon the surface of
the skin composed of a complex mixture of sebum, sweat.
 Three functional layers:
 Epidermis,
 Dermis (true skin)
 Hypodermis
(Subcutaneous fat layer).
 Blood capillaries and
nerve fibers.
 Sweat glands.
 Hair follicles.

The epidermis is the outermost layer of the skin
 0.02 to 5 mm thickness
 It has five layers,
o Barrier layer (stratum germinativum).
 Beneath the hornylayer
 Composed of living epidermal cells.
o Horny layer
(stratum corneum).
 The uppermost layer
Composed of dead epidermal cells forms the permeability barrier

The stratum corneum consists of:
Horny skin cells (corneocytes) which are connected
via protein-rich attachments of the cell membrane.
The corneocytes are embedded in a lipid matrix in
“Brick and mortar” structure.
The corneocytes of hydrated keratin comprise the
bricks and the epidermal lipids fill the space
between the dead cells like mortar.

Routes of skin Penetration
Include transport via:
1- Hair follicles and sebaceous
glands
2- Sweat glands
1 2
These routes avoid penetration through the stratum
corneum and therefore known as shunt routes.
The Transappendageal route:
There are two diffusional routes to penetrate intact skin:

1 2
 Although these routes offer high permeability, they are of
minor importance because of their relatively small area,
0.1% of the total skin area.
The transappendageal route
seems to be most important for
ions and large polar molecules
which hardly permeate through
the stratum corneum.

Transepidermal transport
means that molecules cross
the intact horny layer.

Two potential micro-routes are exist
The transcellular (or intracellular) rout.
The intercellular pathways.
The principal pathway taken by
drugs is decided by its partition
coefficient.
Hydrophilic drugs partition into the intracellular pathways,
whereas lipophilic drugs traverse the stratum corneum via
the intercellular route.

Factors Affecting Percutaneous Absorption
 Factors concerning the nature of the drug
 Factors concerning the nature of the vehicle
 Factors concerning the condition of the skin
Percutaneous absorption is the absorption of substances
from outside the skin to positions beneath the skin,
including entrance into the blood stream.

1. Drug concentration Percutaneous absorption
2. Drug partition coefficient (greater attraction to the skin
than to the vehicle) Percutaneous absorption
3. Molecular weight below 800
Percutaneous absorption
4. Particle Size
5. Solubility in mineral oil and water
 Factors concerning the nature of the drug

1. Spreadability of the vehicle
2. Mixing with the sebum
3. Hydration of the skin Percutaneous absorption
Oleaginous vehicles act as moisture barriers through
which the sweat from the skin cannot pass, thus
increased hydration of the skin beneath the vehicle and
increase Percutaneous absorption.
Factors concerning the nature of the vehicle

 Factors concerning the condition of the skin
Transdermal absorption follow Fick’s First Law of Diffusion
Js = Km D Cs
E
Js = Flux of solute through the skin
Km = Distribution coefficient of drug between vehicle and
stratum corneum
Cs = Concentration difference of solute across the
membrane
D = Membrane Diffusion coefficient for drug in stratum
corneum
E = Thickness of stratum corneum

1. The thickness stratum corneum
2. Multiple application dosing
Percutaneous absorption than single Application
3. Time of contact with the skin
4. Broken skin permit (remove of the stratum corneum)

There are two basic types of transdermal dosing systems:
(1) those that control the rate of drug released to the skin,
(2) those that allow the skin to control the rate of drug
absorption.
Drug delivery systems have been developed to control the
rate of drug delivery to the skin over a period of time for
subsequent absorption.

Percutaneous Absorption Enhancers
Mechanisms of action by which Materials enhance
absorption through stratum corneum is either by
 Enhancing drug release from the formulation to the skin.
 Reduction of the resistance of the stratum corneum by
altering it physicochemical properties

 Alteration of the hydration of the stratum
corneum using occlusive formulations.
 Carrier mechanisms in the transport of ionisable
drugs.
 Enhance absorption by directly influencing
the stratum corneum
(CHEMICALLY or PHYSICALLY).
This can be achieved by the following mechanisms:

Chemicals used to enhance absorption by directly
influencing the stratum corneum
Chemicals interact with the keratin structure in the stratum
corneum and open the tight protein structure, this leads
increase the diffusion coefficient D for substances which use
the transcellular route:
Surfactants, Dimethylsulfoxide (DMSO) and Urea.
Solvents extract lipids and making the stratum corneum more
permeable: Dimethylsulfoxide (DMSO) and Ethanol.

Chemical enhancers which intercalate into the structured
lipids of the horny layer and disrupt the packing. Thus
make the regular structure more fluid and increases the
diffusion coefficient of drugs:
Azone, Oleic acid, and isopropyl myristate
Solvents increase solubility and improve partitioning:
Alcohol, acetone, polyethylene and propylene glycol

Physical methods can enhance drug flux up to several orders
of magnitude above that allowed by passive diffusion (as
conventional skin patches).
The effective delivery range for passive diffusion across the
skin is limited to small, hydrophobic agents,
However, Physical delivery can be used for larger
hydrophilic molecules as peptide drug administration.

IONTOPHORESIS
A physical method to enhance transdermal drug delivery
and penetration.
It involves the delivery of charged chemical compounds across
the skin membrane using an applied electrical field.

Mechanisms of Transport
Iontophoresis uses two electrodes, the anode
and the cathode, each of which is in contact
with a reservoir containing the drug to be
delivered as an electrically conductive
aqueous solution.
The reservoir containing the drug is in contact with the
electrode of the same charge which is (the active electrode),
while the other electrode named (passive electrode).
An electrical potential is applied across the electrodes, causing
current to flow across the skin and facilitating delivery of the
therapeutic agent by repulsion.

Schematic of iontophoretic drug delivery system shows delivery
of an anionic agent from the cathodal reservoir.
The agent goes through the non vascularized epidermis and into
the dermis, where it can be transported into the blood through
the capillary loops.
Cathod
e
Blood
Dermis
Cl-,anions Anionic drug delivered
Indifferent electrode Donor + anionic drug
+ -
Epidermis
Anode
V

Variables affecting iontophoresis:
The electrical current.
Which may be direct, alternate or pulsed
Biological factors:
Involve the presence of thickness,
permeability and porous of the skin.
Physicochemical factors:
Include charge, size, structure and lipophilicity of the drug
with small or large molecular size.
The drug should be water soluble, of low dose and ionizable
with high charge density.

Formulation factors:
Include dug concentration, pH, ionic strength and viscosity.
 Increasing drug concentration results in greater drug
delivery.
 The inclusion of buffer ions in a formula will compete with
the drug for the delivery current and decrease the quantity
of drug delivered, especially since buffer ions are smaller
and more mobile than the large active drug. The pH of the
solution can be adjusted and maintained by large molecules
as ethanolamine : ethanolamine HCL.
 An increase in the ionic strength of the system will increase
the competition for the available current especially when the
active drugs are potent and present in small concentration.

They are also poorly absorbed
from the transdermal route,
because of their large molecular
size, ionic character, and
impenetrability of the skin.
A number of drugs have been used including, lidocaine,
amino acids, peptides and insulin.
These agents are presently delivered by injection, because
of their rapid metabolism and poor absorption following
oral delivery.

SONOPHORESIS
Sonophoresis (Phonophoresis)
in which High-frequency ultrasound,
is used to enhance transdermal drug delivery.
Among the drugs used are hydrocortisone, lidocaine, and
salicyclic acid in the form of gels, creams, e lotions (coupling
agents) followed by ultrasound unit.
The high-frequency ultrasound (1 MHZ at 0.5 to 1 W/cm2) can
disrupt the stratum corneum which influence the integrity of
and thus affect its penetrability.

Involves the formation and collapse of
very small air bubbles in a liquid in
contact with ultrasound waves.
These air bubbles can disperse the
ultrasound waves resulting in heating
at the liquid air interfaces.
Three effects are results from ultrasound include:
Cavitation, microstreaming and heat generation.
Cavitation:

Micro-streaming:
Closely associated with cavitation results in efficient mixing
by inducing vortexes (currents) in small volume elements of
a liquid, this may enhance dissolution of suspended drug
particles results in s higher concentration of drug near the
skin for absorption.
Heat generation:
Heat results from the conversion of ultrasound energy to
heat energy and can occur at the surface of the skin and
deeper layers of the skin.

The vehicle containing the drug must be formulated to
provide good conduction of the ultrasonic energy to the skin.
 The product must be smooth and non-gritty as they will
be rubbed into the skin by the head of the transducer.
 The product should have low viscosity for easy of
application and easy of movement of the transducer (as
gels).
 Emulsions can be used but the oil/ water interfaces can
disperse the ultrasonic waves, resulting in a reduction of
the intensity of the energy reaching the skin. It may case
some localized heat.

Requirements for rate-controlling transdermal
drug delivery systems:
l. Deliver the drug substances at a controlled
rate, to the intact skin of patients, for
absorption into the systemic circulation.
2. The system should possess the proper physicochemical
characteristics to permit the release of the drug
substance and facilitate its partition from the delivery
system into the stratum corneum.
3. The system should occlude the skin to ensure
the one-way flux of the drug substance.

4. The transdermal system should
have a therapeutic advantage
over other dosage forms and drug
delivery systems.
5. The system's adhesive, vehicle,
and active agent should be
nonirritating and non-sensitizing
to the skin of the patient.
6. The patch should adhere well to
the patient's skin.
7. The system should not permit the
proliferation of skin bacteria
beneath the occlusion.

Technology of Transdermal Delivery Patches
Technically, transdermal drug delivery systems may be
categorized into two types:
Monolithic systems
membrane-controlled systems
Monolithic system
Membrane-controlled system

The drug-matrix layer is
composed of a polymeric
material in which the drug
is dispersed.
The polymer matrix controls
the rate at which the drug is
released for percutaneous
absorption.
Monolithic Transdermal Patches
Incorporate a drug matrix layer between backing and
frontal layers.
NicoDerm® CQ®
nicotine transdermal system

Polymer Matrix
The Polymer controls the release of the drug from the device .
Possible useful polymers for transdermal devices are:
A-Natural Polymers :
e.g. Cellulose derivatives, Gelatin, Shellac, Waxes, Proteins,
Gums and their derivatives, Natural rubber, Starch.
B- Synthetic Elastomers :
e.g. Polybutadieine, Styrene butadieine, Polysiloxane, Silicone
rubber, Acrylonitrile, Butyl rubber, Neoprene.
C -Synthetic Polymers :
e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyacrylate,
Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy.

The matrix may be with or without an excess of drug with
regard to its equilibrium solubility and steady-state
concentration gradient at the stratum corneum.
In types having no excess, drug is available to maintain
the saturation of the stratum corneum only as long as
the level of drug in the device exceeds the solubility limit
of the stratum corneum.
As the concentration of drug in the device diminishes
below the skin's saturation limit, the transport of drug
from device to skin gradually declines.

In monolithic systems that have an excess amount of
drug present in the matrix, a drug reserve is present to
assure continued drug saturation at the stratum
corneum, this assures continuous drug availability and
absorption.
The rate of drug decline is less than in the type designed
with no drug reserve.
Examples of monolithic systems are NitroDur (Key) and
Nitrodisc (Searle).

In the preparation of monolithic systems, the drug and the
polymer are dissolved or blended together, cast as the
matrix, and dried.
The gelled matrix may be produced in sheet or cylindrical
form, with individual dosage units cut and assembled
between the backing and frontal layers.

Designed to contain a drug reservoir, usually in
liquid or gel form, a rate-controlling membrane,
and backing, adhesive, and protecting layers.
Examples are Transderm-Nitro (Summit) and
Transderm-Scop (CIBA)
and levonorgestrel/estradiol
for hormonal contraception.
Membrane-controlled Transdermal Patches

Membrane-controlled systems have the advantage over
monolithic systems:
As the drug solution in the reservoir remains saturated, the
release rate of drug through the controlling membrane
remains constant.
 In membrane systems, a small quantity of drug is
frequently placed in the adhesive layer to initiate prompt
drug absorption and pharmaco-therapeutic effects upon skin
placement.
Membrane controlled systems may be prepared by
preconstructing the delivery unit, filling the drug reservoir,
and sealing, or by a process of lamination, which involves a
continuous process of construction, dosing, and sealing.

General Considerations in the proper Use
of Transdermal Drug Delivery Patches:
1. The site for application should be clean, dry, and hairless
(but not shaved).
Nitroglycerin patches are generally applied
to the chest, estradiol to the abdomen,
scopolamine behind the ear,
nicotine to the upper trunk or upper outer arm for
smoking cessation.
Because of the possible of skin irritation, the site of
application must be rotated, that skin sites must not
reused for a week.

2. The transdermal patch should not be applied to skin that
is oily, irritated, cut or abraded to assure the intended
amount and rate of transdermal drug delivery and
absorption.
3. The patch should be removed from its protective package,
being careful not to tear or cut it. The patch's protective
backing should be removed to expose the adhesive layer,
and it should be applied firmly with the palm or heal of
the hand until securely in place.

4. The patient should be instructed to cleanse the hands
before and after applying the patch.
5. Care should be taken not to rub the eyes or touch the
mouth during handling of the patch.

Nanotechnology in Drug
Delivery Systems

Primary goals
• More specific drug targeting
and delivery.
• Reduction in toxicity while
maintaining therapeutic
effects.
• Greater safety and
biocompatibility,
• Faster development of new
safe medicines.

Nanoparticles for
Drug Delivery
• Metal-based nanoparticles
• Lipid-based nanoparticles
• Polymer-based nanoparticles
• Biological nanoparticles

Liposomes and other Lipid-based Nanoparticles
• Self assembling, spherical, closed colloidal structures
composed of lipid bilayers that surround a central aqueous
space.
• Their exterior lipid bilayer is very chemically reactive,
thereby providing a means to conveniently couple “tags” on
a covalent basis.
• A variety of different encapsulants are possible including
visually detectable dyes (since the lipid bilayer is
transparent), optically and fluorometrically detectable dyes,
enzymes, and electroactive compounds.
• First generation liposomes have an unmodified
phospholipid surface that can attract plasma proteins,

• First generation liposomes have an unmodified
• phospholipid surface that can attract plasma
proteins,
• which in turn trigger recognition and uptake by
mononuclear
• phagocytic system (MPS).

Second generation liposomal drugs
• Stealth have hydrophilic
carbohydrates or polymers, which are
derivatives of polyethylene glycol
grafted to the liposomal surface.

Compound Name Status Indication
Liposomal Daunorubicin DaunoXone Market Kaposi’s sarcoma
PEG-Immunoliposome-doxorubicin MCC-465 Phase-I Various cancers
Stealth liposomal doxorubicin Doxil/Caelyx Market Kaposi’s sarcoma; refractory ovarian
&breast cancer
Liposomal doxorubicin Myocet Market (Europe) Metastatic breast cancer in combination
with cyclophosphomide
Liposomal cisplatin SPI-077 Phase II Various cancers
Liposomal interleukin 2 Oncolipin Phase II Immune stimulant
Liposomal thymidylate synthase inhibitor OSI-7904L Phase II Advanced solid cancer
Liposomal paclitaxel LEP ETU Phase I/ II Advanced solid tumors
Liposomal SN38 or liposomal irinotecan
metabolite
LE-SN38 Phase I/ II Advanced solid tumors
Liposomal lurtotecan OSI-211 Phase II Recurrent ovarian cancer
Liposomal oxaliplatin Aroplatin Phase II Advanced colorectal cancer

Micelle
• Micelle is an aggregate of amphipathic molecules in water, with the
nonpolar portions in the interior and the polar portions at the exterior
surface, exposed to water.
• Amphiphilic molecules form micelle above a particular concentration
which is called as critical micellar concentration (CMC).
• Micelles are known to have an anisotropic water distribution within their
structure, means water concentration decreases from the surface
towards the core of the micelle, with a completely hydrophobic (water-
excluded) core.
• Hydrophobic drugs can be encapsulated/solubalized, into inner core.
• The spatial position of a solubilized drug in a micelle will depend on its
polarity, nonpolar molecules will be solubilized in the micellar core, and
substances with intermediate polarity will be distributed along the
surfactant molecules in certain intermediatepositions.

Micelles……
• Beclomethasone diproponate- loaded
polymeric micelles directly administrable
to the lung in nanoparticle sizes in
inhalation dosage form intended to be an
effective in asthma and chronic
pulmonary obstructive disease.

Niosomes
• Niosomes, non-ionic surfactant vesicles, are widely
studied as an alternative to liposomes
• These vesicles appear to be similar to liposomes in
terms of their physical properties
• Niosomes alleviate the disadvantages associated with
liposomes, such as chemical instability, variable purity of
phospholipids and high cost.
• They have the potential for controlled and targated drug
delivery
• Niosomes enhanced the penetration of drugs

Polymeric Nanoparticles
• Drugs are either physically dissolved, entrapped, encapsulated or
covalently attached to the polymer matrix.
• Natural
– Albumin
– Chitosan
– heparin
• Synthetic
– Poly-L-lactide
– Poly-[L-glutamate]
– Poly-[D,L-lactic-co-glycolide]
– PEG

Albumin Paclitaxel Abraxane or ABI-007 Market Metastatic breast cancer
Paclitaxel-poliglumex CT-2103; Xyotax Phase-III Various cancers
PEG-aspartic acid-doxorubicin micelle NK911 Phase-I Pancreatic cancer
HPMA copolymer-doxorubicin PK1; FCE28068 Phase-II Various cancers
HPMA copolymer-doxorubicin-
galactosamine
PK2; FCE28069 Phase-I/II Hepatocellular carcinoma
HPMA copolymer- paclitaxel PNU 166945 Phase-I Various cancers
HPMA copolymer- camptothecin MAG-CPT Phase-I Various cancers
HPMA copolymer- platinate AP5280 Phase-I/II Various cancers
HPMA copolymer- DACH- platinate AP5346 Phase-I/II Various cancers
Dextran- doxorubicin AD-70; DOX-OXD Phase-I Various cancers
Modified- dextran- camptothecin DE-310 Phase-I/II Various cancers

Solid Lipid Nanoparticles (SLN)

• SLN particles made from solid lipids are submicron colloidal carriers
(50-1000nm) dispersed either in water or in aqueous surfactant
solution.
• These consist of solid hydrophobic core having a monolayer of
phospholipid coating.
• The solid core contains drug dissolved or dispersed in the solid high
melting fat matrix.
• The high hydrophobic chains of phospholipids are embedded in the
fat matrix.
• Poloxamer 188, polysorbate 80, lecithin, polyglycerl methylglucose
disterate, sodium cocoamphoacetate.

Adefovir dipivoxil octadeclamine-fluoresin
isothiocyanate
ODA-FITC - Hepatitis B
Chitosan-insulin nanoparticles - - diabetes
Chitosan-coated lipid nanoparticles
containing calcitonin
- - -

Targeted Delivery of Therapeutic
Nanoparticles
• Passive Targeting- takes advantage of the inherent
size of NPs and the unique properties of tumor
vasculature.
– EPR Effect
– Tumor Microenvironment
• Active Targeting- To conjugate a target ligand or an
antibody to NPs.
– Choice of Target Receptor
– Choice of Targeting Ligand

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