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TRANSCRIPT
Novel drug delivery systems, 2nd edition, by Y.W.
Chein page no.: 338 – 380.
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REFERENCES
Transdermal drug delivery systems
Patch
• Definition:
Transdermal drug delivery is defined as a self
contained discrete dosage form, which when applied to
the intact skin, will deliver the drug at a controlled rate to
the systemic circulation.
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Transdermal drug delivery system
POTENTIAL BENEFITS OF
TRANSDERMAL DRUG DELIVERY
(ADVANTAGES)
• Easy to use.
• Avoid GIT absorption problems for drugs.
• Avoids First Pass hepatic metabolism of drugs.
• More improved and convenient patient compliance.
• Rapid termination in case of toxicity is possible.
• Self medication is possible.
• Reduces frequency of dosing.
• Maintains therapeutic level for 1 to 7 days.
• Controlled delivery resulting in more reliable and predictable blood levels.
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DISADVANTAGES
• Daily dose of more than 10mg is not possible.
• Local irritation is a major problem.
• Drug requiring high blood levels are unsuitable.
• Drug with long half life can not be formulated in TDDS.
• Uncomfortable to wear.
• May not be economical.
• Barrier function changes from person to person and within the same person.
• Heat, cold, sweating (perspiring) and showering prevent the patch from sticking to the surface of the skin for more than one day. A new patch has to be applied daily.
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Routes of drug absorption through skin
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Basic components of Transdermal
drug delivery
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BASIC COMPONENTS OF TRANSDERMAL
DRUG DELIVERY SYSTEM
COMPONENT OF TRANSDERMAL DEVICE INCLUDE:
1) POLYMER MATRIX
2) THE DRUG
3) PERMEATION ENHANCER
4) OTHER EXCEPIENTS
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POLYMER MATRIX Following criteria to be considered in selection a polymer:
Molecular weight, physical of polymer must allow
diffusion of drug at desired rate.
Polymer must be non-reactive, inert, non-toxic, easy
to manufacture, inexpensive.
It should not decompose on storage of the device &
not deteriorate when large amount of active ingredient is
in corporated into it.
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LIST OF POLYMERS USED
NATURAL POLYMERS:
Cellulose derivatives, Zein, Gelatin, Shellac, Waxes,
Gums & Natural rubber
SYNTHETIC ELASTOMER POLYBUTADIENE:
Polysiloxane, Silicon rubber, Nitrile, Acrylonitryle,
Butyl rubber, Styrene butadiene rubber.
SYNTHETIC POLYMER
Poly vinyl alcohol, Poly vinyl chloride, Polyethylene,
Poly propylene, Poly urea, PVP, Polymethacrylate
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DRUG
For successful developing transdermal delivery, drug
should be chosen with great care physicochemical
properties
1. Mol. wt. less than 1000 Daltons
2. Affinity for both lipophilic & hydrophilic phase
3. Drug should have low melting point
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Ideal molecular properties for drug penetration
- A low molecular weight (generally less than 500 Daltons) - An adequate solubility in oil and water - A balanced partition coefficient - A low melting point - Potent drug (maximum 10 mg/day) - Half life of drug should be short. - Non irritant to skin. - Drug prone to ‘first pass effect’ and which degrade in GIT are
ideal candidate.
Hormones
• Estradiol and progesterone
• Avoid hepatic metabolism
Cardiovascular drugs
• Hypertension and angina
• Betablockers : timolol, propranolol
• Hepatic metabolism of propranolol
Analgesics
• Control of chronic pain by transdermal therapy
Antihistamines
• Treatment of allergy E.X Chlorpheniramine
• Maintain histamine-receptor antagonism while reducing CNS side
effects such as drowsiness
Central nervous system drugs
• Physostigmine : cholinesterase inhibitors
• To inhibit breakdown of acetylcholine by 30 to 40% over 4days
DRUG
PERMEATION ENHANCERS
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• Vehicle or device to maximize drug partition into the skin
• Incorporate penetration enhancer into formulation\
penetration enhancer are the agents which promote the skin permeability by altering the skin as a barrier to the flux of desired penetrant. Flux J across the skin can be given by J= D. dc/dx D= diffusion coefficient C= concentration x=Spatial coordinate D is function of size, shape, flexibility of diffusing drug molecule
Optimization of Percutaneous Absorption:
IDEAL CHARACTERISTIC OF
PENETRATION ENHANCERS
1) IT SHOULD BE INERT
2) NON-TOXIC, NON- IRRITATING
3) ACTION SHOULD BE IMMEDIATE& PREDICTABLE
4) SHOULD NOT CAUSE REMOVAL OF BODY FLUID
5) SHOLD BE COMPATIBLE WITH DRUG& EXIPIENTS
6) A SUITABLE SOLVENT FOR DRUG
7) SPREAD WELL ON THE SKIN
8) COSMETICALLY ACCEPTABLE
9) ODORLESS, TASTELESS, COLORLESS & CHEAP
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SOLVENTS
The compounds increase penetration possibly by swelling the polar pathway
and fluidizing the lipid
e.g.. Methanol, ethanol, pyrolidiones, propylene glycol, glycerol etc..
SURFACTANTS
They enhance polar pathway transport of hydrophillic drugs
• ANIONIC SURFACTANTS :
Dioctyl sulpho succinate, SLS, decodemethyl sulphoxide
• NON -IONIC SURFACTANTS :
Pluronic F127, pluronic F58
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Backing membrane
They are flexible and provide a good bond to the drug
reservoir, prevent the drug from leaving the dosage form
through top.
It is an impermeable membrane that protects the product
during the use on the skin.
Contains formulation throughout shelf-life and during
wear period
Must be compatible with formulation (non adsorptive)
Printable
E.g.: Metallic plastic laminate , plastic backing with
adsorbent pad adhesive foam pad. 16
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Schematic Skin absorption of drug
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Topical application-absorption & action
of drugs
SYSTEMIC
DRUG IN TARGET TISSUE
DRUG IN BLOOD CIRCULATION
DISTRIBUTION
ELIMINATION
PHARMACOLOGICAL
RESPONSE
TO
PIC
AL
ABSORPTION
DRUG IN DELIVERY
SYSTEM
DRUG IN SKIN SECRETION
FLUIDS, SWEAT, SEBUM,
pH 4.5--5.5
TR
AN
SD
ER
MA
L
LOCALIZED
RELEASE
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FORMULATION APPROACHES
FOR DEVELOPMENT OF
TRANSDERMAL DRUG
DELIVERY SYSTEM
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TYPES OF FORMULATION
PLATFORM FOR THE DRUG:
• Liquids
• Semisolids : ointments and gels
• Non flowing material
That is …
Polymeric film or rubbery gels and
Solid-state platform 20
TYPES OF PLATFORM MONOLITH : slabs, reservoir, vehicle, film, polymer matrix
FILMS :
Natural or synthetic
Porous and non porous
ADHESIVES: viscoelastic materials which remains permanently tacky
E.g. Natural or synthetic rubber, polyacrylates and silicon elastomer
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1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
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The drug reservoir is sandwiched between a drug impermeable
backing laminate and a rate controlling polymeric membrane.
The drug molecules are permitted to release only through the
membrane.
The drug reservoir compartment: The drug is:
1. Dispersed in solid polymer matrix (polyisobutylene)
2. Suspended in unleachable viscous liquid (silicone fluid) to
form paste like suspension.
3. Dissolved in a releasable solvent (alkyl alcohol) to form a
clear drug solution
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1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
The membrane:
Microporous or non porous ploymeric (ethylene -vinyl acetate copolymer).
A thin layer of drug compatible, hypoallergenic
adhesive polymer e.g. Silicon or polyacrylet adhesive
may be applied to the external surface.
Rate of drug release affect by varying the polymer
composition, permeability coefficient and thickness
of rate limiting membrane and adhesive.
Accidental breakage of the rate controlling membrane
can result in dose dumping or a rapid release of the
entire drug content.
E.g.
Nitroglycerine releasing trans dermal system for once
a day medication for angina
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Scopolamine-releasing transdermal system for 72 hr.
prophylaxis of motion sickness.
Clonidine releasing transdermal system for 7 day
therapy of hypertension.
Estradiol-releasing transdermal system for treatment
of menopausal syndrome for 3-4 days.
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The intrinsic rate of the drug release from this type of drug delivery system is defined by
dq CR
dt 1/pm + 1/pa
=
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Pm and pa respectively defined as….
pm km/r . Dm
hm
ka/m . Da
ha
=
= pa
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Where,
Km/r and ka/m are the partition coefficient for the
interfacial partitioning of the drug from reservoir to
the membrane and from the membrane to adhesive
layer respectively.
Dm and Da are diffusion coefficient and
hm and ha are the thickness
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Substituting the pm and pa equation in equation 1
dq km/r . Ka/m . Dm . Da
dt km/r. Dm. ha + ka/m . Da . hm
Which define the intrinsic rate of drug release from a
membrane moderated drug delivery system.
If the membrane is porous, porosity and tortuosity of
the membrane should be taken inconsideration.
= cr
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2. POLYMER MATRIX DIFFUSION
CONTROLLED TDDS SYSTEM
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The drug reservoir:
Homogeneous dispersion of the drug solids in hydrophilic or lipophilic polymer matrix, and the medicated polymer is then molded into medicated discs with defined surface area and thickness.
Then mounted onto impermeable plastic backing.
The adhesive polymer is applied to the circumference of the patch.
E.g. of this type of system is nitro-dur I and nitro-
dur II. for continuous transdermal fusion of
nitroglycerine at a daily dose of 0.5 mg/cm2 for
therapy of angina pectoris.
Nitro dur II is modified version of I in which the drug
is dispersed in acrylic based polymer adhesive with a
resinous cross linking agent which result in much
thinner and more elegant patch.
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The rate of drug release from this type of system is
defined as:
A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp are
the solubility and diffusivity of the drug polymer respectively.
Since only the drug species dissolved in the polymer can release , Cp is equal to CR.
At steady state, Q versus t1/2 drug release profile is obtained. (non zero order
release).
1/2
= dq ACp Dp
dt 2t
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3. ADHESIVE DISPERSION-TYPE
SYSTEM
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e.g. of adhesive polymer is poly(isobutylene) or
poly(Acrylet) adhesive
E.g. of this type of system is isosorbide dinitrate
releasing transdermal therapeutic system for once a
day medication of angina pectoris.
It is used for the administration of verapamil.
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The rate of drug release in this system is defined by:
dQ ka/r . Da
dt ha
where,
Ka/r is partition coefficient for the interfacial partitioning
of the drug from the reservoir layer to adhesive layer.
= cr
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4. GRADIENT CONTROLLED TDDS
Drug – impermeable metallic plastic laminate
Drug reservoir
gradient layers
R1>R2>R3
R1 R1
R2
R3
} 39
The rate of drug release from this drug reservoir gradient controlled system is given by:
dQ ka/r . Ds dt ha (t)
Thickness of the adhesive layer for drug molecules to diffuse through increases with time h(t)
E.g. Nitroglycerine TDD patch
A (ha) =
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To overcome the non zero order release, the drug loading level in the reservoir is varied incrementally.
The thickness of the diffusional path increases with time, to compensate for this, the drug loading level in the multilaminate adhesive layer is increased
Deponit system: nitroglycerin releasing TDDS.
5. MICRORESERVIOR TYPE OR
MICROSEALED DISSOLUTION CONTROLLED
SYSTEM
rim
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Hybrid of reservoir and matrix dispersion type.
The drug is suspended in aqueous solution of water miscible drug solubilizer, then dispersing the drug suspension in a lipophilic polymer by shear mechanical force to form thousands of microscopic drug reservoirs.
The medicated disc is then mounted at the center of an adhesive pad.
It is successfully utilized in the preparation of nitro-
disc, a nitroglycerine releasing trans dermal
therapeutic system used in angina pectoris.
This system followed zero order release of drug
without the danger of dose dumping.
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Choose a dry, unbroken, non-hairy part of your skin. The buttocks, lower abdomen, lower back, and upper arm (outer part) are good choices. If the area you choose has body hair, clip (do not shave) the hair close to the skin with scissors.
the area is clean. If there is any oil or powder (from bath products, for example), the patch may not stick properly.
Attach the adhesive side of the patch to skin in the chosen area.
Find an appropriate place to put the patch
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Find an appropriate place to put the patch
ADVANCED RESEARCHES
MICROARRAY NEEDLE
Advanced micro-needle Patch transdermal system
allowing continuous delivery through the skin of
proteins and water-soluble drugs.
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• The device create painlessly micropores in the S.C.
known as microstructered arrays or microneedles.
• These devices have about 400 microneedles.
• The solid silicone needles (coated with drug) or
hollow metal needles (filled with drug solution)
penetrate the horny layer without breaking it or
stimulating nerves in deeper tissues.
• Flux increase up to 1,00,000 fold are reported.
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ADVANCED RESEARCHES
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MICRONEEDLE ARRAY
MICRO TRANS
Applications :
Delivery of large proteins, fragile antibodies, and
hormones.
Delivery of small molecules, particularly those
with difficulty diffusing through skin layers.
Delivery of vaccines, both conventional and DNA-
based.
Fluid sensing of glucose, hormones, blood gases,
and therapeutic drug levels.
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Liposomes and vehicles Liposome are colloidal particles formed as concentric
bimolecular layers that are capable of encapsulating
drugs.
There are many examples of cosmetic products in which the active
ingredients are encapsulated in vesicles. These include humectants such as
glycerol and urea, sunscreening and tanning agents, enzymes, etc.
Phosphatidylcholine from soybean or egg yolk is the most common
composition although many other potential ingredients have been evaluated .
Cholesterol added to the composition tends to stabilize the structure thereby
generating more rigid liposomes.
Solid lipid nanoparticles Solid lipid nanoparticles (SLN) have recently been investigated as carriers for
enhanced skin delivery of sunscreens, vitamins A and E, triptolide and
glucocorticoids.
It is thought their enhanced skin penetration is primarily due to an increase in
skin hydration caused by the occlusive film formed on the skin surface