NDDS TOPICS BY PROF. SHASHANK CHAURASIYA

1. TRANSDERMAL
DRUG DELIVERY
SYSTEMS
PREPARED BY:
PROF. SHASHANK CHAURASIYA
BANSAL COLLEGE OF PHARMAY, BHOPAL

2.  Introduction
 Advantages & Disadvantages
 Skin & Drug Permeation
 Percutaneous Absorption & Kinetics
 Factor Affecting Percutaneous Absorption
 Basic Components Of TDDS
 Types Of Transdermal Patch
 Formulation Approaches Used In Development Of TDDS
 Marketed Products
 Patents & Recent Research
CONTENTS

3. INTRODUCTI
ON TDDS facilitate the passage of therapeutic quantities of drug
substance through the skin and into the general circulation for their
systemic effects.
 In 1965 Stoughton first conceived of the percutaneous
absorption of drug substance.
 The first transdermal system, Transderm Scop (Ciba, now Novartis)
was approved by the FDA in 1979 for prevention of nausea and
vomiting associated with travel, particularly by sea.

4. Substitute for
oral
administration
Avoid the first-pass
effect
Delivers a steady
infusion of a drug
Self administration is
possibleDrug therapy may be
terminated rapidly
Improved patient
compliance
Lack of peaks in plasma
concentration (the riskof
side effects)
Used for drugs with
narrow therapeutic
window

5. Cannot use for
large molecule
(>500 Dalton)
Cannot be used for
drugs requiringhigh
blood levels
Long time adherenceis
difficult
Higher cost
Variation in
absorption efficiency
a different sites of
skin
Cannot
deliverionic
drugs
Skin irritation or
contact dermatitismay
occur
Natural limits of drug
entry imposed by the
skin’simpermeability

6. Epiderm
is
Dermi
s
Hypoderm
is
SKI
N
 Stratum Corneum
 Stratum Lucidum
 Stratum Granulosum
 Stratum Spinosum
 Stratum Basale
 Blood vessels
 Sweat glands
 Hair follicle
 Sebaceous glands
 Adipose Tissue
 Artery
 Vein
Anatomy & Physiology Of
Skin

7. Skin

9. Routes Of Skin Permeation

10. Product/Device
Solute Vehicle
Stratum
Corneum
Penetration
Epidermis &Upper
Dermis Concentration
Systemic Blood Concentration
Hair Follicles,
Sweat Ducts
Therapeutic
Activity
Tissues
Underlying
Subcutaneou
s &Muscles
Device, Solute, Vehicle
Determination of Permeability
Desquamation Release
Target Delivery
Effects on Skin
Turnover Lipids
Diffusion Local Blood
Flow
Dermal Blood Flow
Epidermal & Dermal Metabolism
Action
Distribution
Metabolites Urine etc.
Clearance
Toxicity

11. Skin permeation kinetics is vital to the successful development of transdermal therapeutic
system. Transdermal permeation of drug involve following steps –
1) Sorption by stratum corneum.
2) Penetration of drug through viable epidermis.
3) Uptake of drug by capillary network in dermal papillarylayer.
The rate of permeation across the skin (dq/dt) is given by –
dq/dt = Ps (Cd-Cr)……………………..(1)
Where Cd and Cr are, the concentration of skin penetrant in the donor compartment and in
the receptor compartment respectively
Ps permeability coefficient
Kinetics Of Transdermal Permeation

12. Permeability coefficient is given by the relationship: -
Ps =Ks Dss / hs…………………………… (2)
Where Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule
from a solution medium or a transdermal therapeutic system ,
Dss is the apparent diffusivity for the steady-state diffusion of the penetrant molecule through
a thickness of skin tissues
hs overall thickness of skin tissues
Ks, Dss and hs are constant under given conditions, the Ps should be constant.
From equation (1) it is clear that a Cd>>Cr i.e., the drug concentration at the surface of the
stratum corneum (Cd) is consistently and substantially greater than the drug concentration in
the body (Cr). Then equation (1) becomes.
dq/dt = Ps Cd ………………(3)
(dq/dt) is constant provided the magnitude of Cd remains fairly constant throughout the
course of skin permeation. For keeping Cd constant, the drug should be released from the
devices at a rate (Rr) that is either constant or greater than the rate of skin uptake (Ra) i.e.,
Rr>>Ra.

13. Since Rr>>Ra , the drug concentration on the skin surface (Cd) is maintained at a level equal to
or greater than the equilibrium solubility of the drug in the stratum corneum (Cs) i.e., Cd>>Cs.
Therefore, a maximum rate of skin permeation [(dq/dt) m] is obtained and is given by the
equation: -
(dq/dt) m = Ps Cs ……………… (4)
(dq/dt) m depends on (Ps) and its equilibrium solubility in the stratum corneum (Cs).
Thus skin permeation appears to be stratum corneum-limited.

14. Skin conditions Skin hydration Sunlight
Skin age Temperature and pH Cold
season
Regional skin site Diffusion coefficient Air
pollution
Skin metabolism Drug concentration Effect of
heat
Partition coefficient
Molecular size and
shape

15. Components Of TDDS
The components of transdermal devices include.
1. Polymer matrix / Drug reservoir
2. Drug
3. Permeation enhancers
4. Pressure sensitive adhesives
5. Backing laminate
6. Release liner
7. Other excipients

16. Polymer Matrix
Ideal properties of a polymer to be used in a transdermal system
-
 Molecular weight, chemical functionality of the polymer should be such that the
specific drug diffuses properly and gets released through it.
 Stable, non-reactive with the drug.
 Non-toxic or non- antagonistic to the host.
 Easily of manufactured and fabricated into the desired product.
 Inexpensive.
 Large amounts of the active agent are incorporated into it.

17. Commonly Used Polymers For Transdermal Devices
Natural Polymers Synthetic Elastomers Synthetic Polymers
Cellulose derivatives
Arabino Galactan
Zein
Gelatin
Proteins
Shellac
Strarch
Polybutadiene
Hydrin rubber
Polysiloxane
Acrylonitrile
Neoprene
Chloroprene
Silicon rubber
Polyvinyl alcohol
Polyethylene
Polyvinyl Chloride
Polyacrylates
Polyamide
Polyurea
Polyvinlypyrrolidone

18. Drug Substance
Parameter
Dose
Half life
Molecular weight
Melting point
Partition coefficient
Aqueous Solubility
pH of the aqueous saturated solution
Skin Permeability Coefficient
Skin Reaction
Oral Bioavailability
Properties
Less than 20 mg/day
< 10 hrs
<400 Dalton
<200°C
1 to 4
>1mg/mL
5-9
>0.5×10-3cm/h
Non irritating and non-sensitizing
Low
Ideal Properties Of Drug Candidate For Transdermal Drug Delivery

19. Permeation Enhancers
These are compounds which promote skin permeability by altering the skin as a
Barrier to the flux of desired penetrants.
The flux, J, of drugs across the skin can be written as -
Where D = diffusion coefficient
C = concentration of the diffusing species
x = spatial coordinate
Enhancement of flux across membranes reduces to considerations them as
follows -
1. Molecular size and shape.
2. Reducing the energy required to make a molecular hole in the membrane.
3. Thermodynamics (lattice energies, distribution coefficients).

20. Types Of Absorption Enhancers
Class Examples Mechanism
Surfactants Anionic : Sodium lauryl sulphate Transcellular
Nonionic : Pluronic F68 & F127 Transcellular
Bile Salts : Sodium deoxycholate , Sodium Paracellular
taurocholate
Solvents Methanol, Ethanol, Propylene glycol, Transcellular
Glycerol etc.
Cyclodextrins Methylated b cyclodextrins, Paracellular
a-, b- and g cyclodextrins Transcelular
Chelating agents EDTA, Transcellular
Polyacrylates Paracellular
Positively charged polymer
Chitosan salts,
Trimethyl chitosan
Paracellular

21. Pressure Sensitive Adhesive
PSA helps in maintaining an intimate contact between transdermal system
and the skin surface.
 It should be removable from the smooth surface without leaving a residue
e.g.: polyacrylamates, polyacrylates, polyisobutylene, silicone based adhesive.
 The selection is based on numerous factors, including the patch design and
drug formulation.
PSA should be physicochemical and biologically compatible and should not
alter drug release.

22. While designing a backing layer the consideration of chemical resistance and
excipients may compatible because the prolonged contact between the backing
layer and the excipients, drug or penetration enhancer through the layer.
They should a low moisture vapour transmission rate. They must have optimal
elasticity, flexibility and tensile strength. eg: aluminium vapour coated layer, a
plastic film and heat real layer.
Release Linear
Prevents the loss of drug that has migrated into the adhesive layer and
contamination. However, as the linear is in intimate contact with the delivery
system, it should comply with specific requirements regarding chemical inertness
and permeation to the drug, penetration enhancer and water.
Backing Laminates

23. Other Excipients
Various solvents such as chloroform, methanol, acetone, isopropanol and
dichloromethane are used to prepare drug reservoir.
In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethylene
glycol and propylene glycol are added to provide plasticity to the transdermal
patch.

24. Types Of Transdermal Patch
1. Single-layer Drug-in-Adhesive
 The adhesive layer of this system also contains the drug.
 Adhesive layer not only serves to adhere the various layers together, along with the
entire system to the skin, but is also responsible for the releasing of the drug.
 The adhesive layer is surrounded by a temporary liner and a backing.
 Example- Deponit

25. 2. Multi-layer Drug-in-Adhesive
Similar to the single-layer system in that both adhesive layers are also responsible
for the releasing of the drug.
It adds another layer of drug-in-adhesive, usually separated by a membrane (but
not in all cases).
 This patch also has a temporary liner-layer and a permanent backing.
 Example- Nicotrol

26. 3. Reservoir
 Reservoir transdermal system has a separate drug layer.
 The drug layer is a liquid compartment containing a drug solution or suspension
separated by the adhesive layer.
This patch is also backed by the backing layer. In this type of system the rate of release
is zero order.
 Example- Transderm-Nitro

27. 4. Matrix
The Matrix system has a drug layer of a semisolid matrix containing a drug solution
or suspension.
 The adhesive layer in this patch surrounds the drug layer partially overlaying it.
 Example- Nitro-Dur

28. 5. Vapour Patch
Adhesive layer not only serves to adhere the various layers together but also
to release vapour.
The vapour patches are new on the market and they release essential oils for
up to 6 hours & used in cases of decongestion mainly.
Other vapour patches on the market are controller vapour patches that
improve the quality of sleep. Vapour patches that reduce the quantity of
cigarettes that one smokes in a month are also available on the market.

29. Approaches Used In Development Of TDDS
1.
• Membrane permeation – controlled systems
2.
• Adhesive dispersion – type systems
3.
• Matrix diffusion – controlled systems
4.
• Microreservoir type or Microsealed dissolution – controlled
systems

30. Example:
I. Nitroglycerine-releasing Transdermal system (Transderm-nitro) for once a day
medication in angina pectoris.
II. Scopolamine-releasing Transdermal system (Transderm-scop) for 72 hrs.
Prophylaxis of motion sickness.

31. The drug reservoir is formulated by directly dispersing the drug in an adhesive polymer &
then spreading the medicated adhesive by hot melt, on to a flat sheet of drug impermeable
metallic plastic backing to form a thin drug reservoir layer.
Example: Isosorbide dinitrate-releasing transdermal therapeutic system (Frandol tape) for
once a day medication of angina pectoris.

32. It is prepared by homogeneously dispersing the drug particles with a liquid polymer or a
highly viscous base polymer followed by cross linking of the polymer chains or
homogeneously blending the drug solids with a rubbery polymer at an elevated
temperature.
Example: Nitrogiycerine-releasing transdermal system (Nitro- Dur and Nitro- Dur II) a
daily dose of 0.5 mg/cm2 for therapy of angina pectoris.

33.  It is combination of reservoir & matrix diffusion type drug delivery system.
Drug reservoir is formed by first suspending the drug solids in an aqueous solution of a
water soluble liquid polymer & then dispersing the drug suspension homogeneously in a
lipophilic polymer such as silicone elastomers by high energy dispersion technique.
Example: Nitroglycerine-releasing transdermal system (Nitro disc) for once a day of
angina pectoris.

34. Marketed Products
Therapeutic
Agent
Brand Name Manufacturer Name Indication
Clonidine Catapres-TTS Boehringer Ingelheim Hypertension
Estradiol Estraderm Novartis Postmenstr
ual syndrom
Vivelle Novartis
Fentanyl E-Trans Alza Corporation Moderate/severe pain
Duragesic Alza/Janssen
Pharmaceutica
Nicotine Habitrol Novartis Smoking cessation
Nicotrol McNeil Consumer

35. Nicoderm CQ GlaxoSmithKline
Nitroglycerine Deponit Schwarz Pharma Angina pectoris
Nitro-Dur Key pharmaceutical
Transderm-Nitro Novartis
Testosterone Testoderm Alza corporation Hypogonadism in
male
Androderm GlaxoSmithKline
Scopolamine Transderm-Scop Novartis Motion sickness
Lidocaine Sona Prep Echo Therapeutics Local anesthetic

36. Insulin Sono Derm Imarx Diabetes
Powderject Powderject Pharmaceuticals
Estrogen Nuvelle-TS Ethical Holding/Schering Postmenstr
ual syndrom

37. Patent No. Invento Novelty
20060135911 Mittur et al Prepared a device which is known as a trans-body-surface
drug delivery device including a reservoir having at least one
drug and a thermo effector having a first surface.
20050186262 Osborne et al Prepared a transdermal delivery device for treatment of
hypertension with the drug delivery of dihydropyridine-type
calcium antagonist through the skin .
20120277695 Cottrell et al Prepared a transdermal patch for administration of an opioid
the composition comprising a phosphate compound of
tocopherol and a polymer carrier .
8252319 Yum et al The invention relates to the transdermal delivery of
Sufentanil which provides sufficient amount of sufentanil to
induce and maintain analgesia for extended periods when
applied to a subject .

38. 4956171 Chang, Yunik Describes transdermal drug delivery system with dual
permeation enhancers and has a basal surface that contacts an
area of skin and transmits the drug . The dual permeation
enhancers used are sucrose cocoate& methyl laurate .

39. Recent Research Reports From Pubmed
Drug Polymer or Major
Excipients
Type of Patch and
Preparation
Method
Remarks Reference
Domperidone HPMC & Eudragit RL Bilayered matrix type Patchs Madishetti
100 (polymer), d- patchs & Film casting prepared with et al , 2010
limonene method the required
(permeation
enhancer)
fiux (86.02
ug/hr/cm2)&
permeation
coefficient
(0.86x10-2
cm/hr)
Lercanidipine HPMC & Eudragit RL Matrix type & To determine Mamatha et
hydrochloride 100 (polymer), d- Solvent evaporation the effect of al , 2010
limonene technique penetration
(permeation enhancer,
enhancer) limonene on
drug
permeation

41. .
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