This document discusses transdermal drug delivery, including the structure of human skin, theoretical advantages of transdermal delivery, optimization of percutaneous absorption, development of transdermal therapeutic systems, examples of applications, and recent advances. The key points are: human skin consists of the epidermis and dermis, with the stratum corneum acting as the rate-limiting barrier; transdermal delivery provides controlled drug levels, avoids first-pass metabolism, and increases compliance; penetration is optimized through formulations incorporating penetration enhancers and appropriate vehicles; transdermal systems can provide sustained delivery through reservoirs, matrices, and membranes; examples of drugs delivered this way include scopolamine, nitroglycerin, estradiol and

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