1. Transdermal Drug Delivery
PRESENTED BY:
GANDHI SONAM MUKESHCHANDRA
M.PHARM [INDUSTRIAL PHARMACY]

2. Transdermal Drug Delivery
 The structure of Human Skin
 Theoretical advantages of the transdermal
route
 Optimization of percutaneous absorption
 Development of the transdermal therapeutic
system
 Examples of transdermal applications
 Other transdermal systems
 Recent advances

3. I. Introduction
 Transdermal permeation (percutaneous absorption)
 The passage of substance from the outside of the skin through
its various layers into the bloodstream
 Advantages of transdermal delivery system
 The system avoids the chemically hostile GI environment
 No Gi distress or other physiological contraindications of the oral
route
 Can provide adequate absorption of certain drugs
 Increased patient compliance
 Avoids first-pass effect
 Allows effective use of drugs with short biological half-life
 Allow administration of drugs with narrow therapeutic windows
 Provides controlled plasma levels of very potent drugs
 Drug input can be promptly interrupted when toxicity occurs

4.  Disadvantages of TDS
 Drug that require high blood levels cannot be administered
 Adhesive may not adhere well to all types of skin
 Drug or drug formulation may cause skin irritation or
sensitization
 Uncomfortable to wear
 May not be economical
 Consideration of TDS development
 Bioactivity of drug
 Skin characteristics
 Formulation
 Adhesion
 System design
 Factors influence the permeation of drugs
 Skin structure and its properties
 The penetrating molecule and its physical-chemical relationship
to skin and the delivery platform
 The platform or delivery system carrying the penetrant
 The combination of skin, penetrant, and delivery system

5. II. The Structure of Human Skin
 Human skin
 The stratified avascular cellular epidermis
 An underlying dermis of connective tissue
 Stratum corneum or horny layer
 Rate-limiting or slowest step in the penetration process
 Transport mechanism
 Transepidermal pathway across the horny layer either
intra- or intercellularly
 Via hair folicles and sweat glands (the appendageal route)

6. Fig. 1 Basic diagram of skin structure.

7.  Factor influence the transdermal route
 Time scale of permeation (steady-state vs. transient
diffusion)
 Physicochemical properties of penetrant (pKa, molecular
size, stability, binding affinity, solubility, partition
coefficient)
 Integrity and thickness of stratum corneum
 Density of sweat glands and folicles
 Skin hydration
 Metabolism
 Vehicle effects
 Stable preparation of TDS
 Correct partition coefficient relative to the drug reservoir,
device membrane and skin layers
 Rate-controlling membrane : low flux (skin act as a sink)
 Impermeability of stratum corneum : individual patient’s
skin control drug input and significant biological variability

8.  Partition into skin
 Prodrugs with low melting points
 Penetration-enhancing substances
 Microenviornment of the skin surface
 Light, oxygen, bacteria
 Change in skin flora with maceration and irritation of the
skin – sweat gland ineffective
 Enzyme (80 to 90% as efficient as in the liver)
 Hydrolytic, oxidative, reductive and conjugative reaction
 Incorporate enzyme inhibitors

9. III. Theoretical Advantages of the
Transdermal Route
 Variables associated with GI absorption
 First-pass effect
 Changes in pH
 Gastric emptying, intestinal motility and transit time
 Activity of human and bacterial enzymes
 Influence of food
 Percutaneous administration
 Control administration and limit pharmacological action
 Minimize pulse entry of a drug into the bloodstream
 Not deliberately provide a control on/off action
 Skin membranes : slow-response system with prolonged
lag time

10. Fig. 2. Process of transdermal permeation.

11. IV. Optimization of Percutaneous
Absorption
 Formulation of dermatological preparations
 Vehicle or device to maximize drug partition into the skin
 Incorporate penetration enhancer into formulation
 Enhancers
 Phamacologically inert, not interacting with receptors
 Neither toxic, irritating nor allergenic
 The onset of enhancer activity and the duration of effect :
predictable and controllable
 Skin : immediate and full recovery
 Promote penetration without problems of loss of body fluids,
electrolytes or other endogeneous materials
 Compatible with drug and adjuvants
 A suitable solvent for drug
 Spread well on the skin
 Formulate into cream, ointment, gel, lotion, suspension, aerosol, etc
 Odorless, tasteless, colorless, inexpensive

12. V. The Theory for Penetration-
Enhancer Activity
 Activity of penetration enhancers
 Interaction with the polar head groups of lipid via
hydrogen and ionic bonding
 Change in hydration sphere of lipids and affect the
packing at the head region
 Increase volume of the aqueous layer : swelling
and hydration
 Alter the packing of the lipid tails  disorder and
traverse by a lipid-like penetrant

13.  Solvents
 DMSO, propylene glycol, ethanol
 Partition coefficient elevate drug concentration in the skin
 Cosolvent
 Azone (1-dodecylazacycloheptane-2-one)
 Cis-unsaturated oleic acid
 Additive : PG  increase solubilizing ability for lipid-like
materials
 Flip over to insert between the hydrophobic groups of the
membrane lipids  increasing fluidity of lipid
 Interaction mechanism of solvents and surfactants
with proteins
 Interaction with polar groups
 Relaxation of binding forces and alterations in helix
conformations
 Pore route formation

14. VI. Development of the Transdermal
Therapeutic System
A. Transdermal Penetration of Drugs
 Percutaneous absorption via diffusion
 Transcellular penetration through stratum
corneum
 Intercellular penetration through stratum corneum
 Transappendageal penetration including the
subaceous pathway and aqueous pathway of the
salty sweat glands

15. B. Formulation
 Platform for the drug
 A liquid : well-constrained
 A semisolid : ointment, semisolid gel
 A non-flowing material
 Polymeric film or rubbery gels
 Solid-state platform
 Combination
 Types of platform
 Monolith, slabs, reservoirs, vehicles, films, polymer matrix
 Films : nature (natural or synthetic), structure (porous or
nonporous)

16. C. Adhesion
 Adhesion
 Good skin contact
 Good bonding between laminating layers
 Properties of pressure-sensitive adhesives
 Adhesive-cohesive properties
 Peel strength
 Tack and creep quality of adhesive
 Occlusive (serve as barrier such as vinyl, PE, polyester
film)
 Nonocclusive (allow water and gases to flow through films)

17.  Pressure-sensitive adhesive
 ASTM (American Society for Testing and Materials)
definition : viscoelastic material which remains
permanently tacky
 Remove from a surface without leaving a residue
 Natural or synthetic rubbers, polyacrylates, silicone
 Release liner (release paper, peel-away strip)
 Sheet that serve as a protectant or carrier for an adhesive
film (easily removed)
 Paper, polystyrene or polyester films with coating of
silicone, long-chain branched polymers, chromium
complex, fluorochemicals or various hard polymers

18. D. Bioactivity
 Trandermal drug delivery
 Minimize the fluctuating levels of drug in the
blood
 Provide drug level within the limits of the
therapeutic windows
 Pharmacokinetic view
 Prolonged steady-state blood levels by adjusting
drug loading, vehicle components, and surface
area

19. VII. Examples of Transdermal
Applications
 Monolithic systems
 Nitrodur and Nitrodisc
 Manufacture drug reservoir with polymer with
subsequent casting and drying
 Punch from sheet or sliced cylinder
 Assembled with the system backing, peripheral
adhesive and protective liner
 Membrane-controlled transdermal system
 Transderm-Nitro, Transderm-Scop
 Form-fill-seal from lamination process

20. Fig. 3. Types of transdermal delivery devices.

21.  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
 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 4d

22. Table 1 Transdermal Controlled-
Release Products and Devices
Drug Trade Name Type of Devices Indication
Scopolamine Transderm-Scop Reservoir Motion sickness
Nitroglycerine Transderm-Nitro Reservoir Angina
Nitro-Dur Monolithic
Nitrodisc Monolithic
Estradiol Estraderm Reservoir and Hormone
ethanol treatment
enhancer

23. Table 2 Transdermal Products under
Development
Drug Trade name Producer-Marketer
Minocycline Sunstar American Cyanamide, Takeda
Estradiol+Noret Estracombi Ciba-Geigy, Alza
histerone TIS
DHEA Pharmedic
Fentanyl
Triamcinolone Whitby Pharm.
acetonide

24.  Drug development using TTS
 Ketoprofen, 5-Fu, metoprolol, terodiline, primaquine, ibuprofen,
piconol, nitrendipine, diclofenac, corticosteroids, sandimune
(cyclosporine A), fluazifopbutyl, glyceryl trinitrate, azo-profen
esters, methotrexate, medroxyprogesterone acetate,
levonorgestrel, mepindolol, oxycodone, prostaglandins, 9-β-D-
arabinofuranosyladenine (Ara-A)
 Iontophoresis
 Built-in battery layer
 Comparable in size to a normal transdermal patch
 The Lectro Patch, General Medical Co.
 Treatment time : 20 min
 Recommended maximum current : 4mA
 Lidocaine (local anesthesia), dexamethasone (arthritis),
hydrocortisone (arthritis), acetic acid (calcified tendinitis) etc.

25. Fig. 4. Schematic diagram illustrating the
principles of iontophoresis.

26. VIII. Other Transdermal Systems
 Lectec Co.
 A solid-state, hydrophilic reservoir system
 Health-Chem Co.
 Transdermal laminar system
 Elan Co.
 Absorbed from bracelets by electrical impulses
 Molecular Biotech Co.
 Proplastic membrane (molecular sponge)

27. IX. Recent Advances
 Rolf
 Amphoteric enhancers : SLS, lauryl amine oxide, Azone
decylmethylsulfoxide, lauryl ethoxylate, octanol
 PSA (pressure sensitive adhesives)
 Adhesive matrix, multilaminated PSA matrix
 Adverse interaction between the drug, exicipents,
cosolvents and permeation enhancers in reservoir and
matrix-type system
 Silicone PSA : tack, adhesion, cohesive strength
 Polydimethylsioxane PSA : biocompatibility and high
permeability

28.  Actiderm (Bristol Myers Squibb)
 Path with no drug as occlusive dressing
 Placed over topically applied corticosterids to enhance
efficacy by promoting hydration of the stratum corneum
 Laminated reservoir system by Hercon
 Steady-state blood levels for extended periods
 Two or four layers, including a backing membrane, the
drug reservoir, a rate-controlling membrane, and an
adhesive
 Ketobemidone and carbonate ester prodrug
 Prodrug with isopropyl myristate, ethanol and ethanol-
water readily penetrate the skin
 Enzymatic conversion, high solubility of prodrug in polar
and apolar solvents

29. X. Conclusion
 Critical parameter in designing a TDS
 Drug stability, physical stability of the formulation, irritation
and sensitization properties, preservation and esthetic
acceptability
 Vehicle affect drug bioavailability
 Maximizing drug penetration into skin
 Two mechanism that manipulate the diffusion of a
drug across the skin
 Change the degree of interaction between drug and
vehicle
(drug’s thermodynamic activity)
 Changes in the stratum corneum that will affect its
diffusional resistance (vehicle-barrier interaction)

30.  Transdermal therapy
 70% or more of all drugs : potentially delivered by
TDS
 Limitation : drug potency, skin permeability,
topical reaction, cutaneous metabolism, delivery
by small volume of skin
 Further TTS : use of prodrug, penetration
enhancer and specific nontoxic enzyme inhibitors
 Peptide delivery
 biotechnology
 Penetration enhancer and iontophoresis

31. THANK YOU